Disease activity assessment in systemic lupus erythematosus

Systemic lupus erythematosus (SLE, lupus) is a chronic autoimmune disease characterised by a heterogeneous clinical presentation and complex underlying immunologic dysfunction. This poses a significant challenge to the accurate assessment of disease activity, which is central to both clinical management and research in SLE. This review aims to describe common barriers to accurately measuring disease activity in SLE and different approaches to disease activity assessment. We will cover the evaluation of disease activity in clinical practice and discuss the role of widely used and emerging disease activity instruments in both clinical and research contexts, including measures of flare, treat-to-target disease states and clinical trial endpoints.

Introduction to SLE and disease activity

SLE is a multisystem disease associated with substantial individual and public health burden. The global prevalence approximates 1 in 2000 (1). SLE is most frequently diagnosed in women aged 15–44 years (2) and is more common in patients of non-Caucasian ancestry (2, 3). The pathophysiology of SLE is incompletely understood, but numerous genetic and environmental risk factors have been identified. Immunological dysfunction, including autoantibody production, culminates in tissue inflammation across a range of organ systems, leading to the diverse manifestations that characterise the disease (4).

The diagnosis of SLE is based on a combination of consistent clinical features and characteristic immunologic findings, such as anti-nuclear (ANA), anti-double stranded DNA (dsDNA) and anti-Smith antibodies, and/or low complement levels. Mucocutaneous and musculoskeletal manifestations affect up to 90% of SLE patients, while lupus nephritis, haematologic disorders, constitutional symptoms and serositis also occur frequently (5). Less common features include neuropsychiatric, cardio-pulmonary, ophthalmic and gastrointestinal involvement, although rates of different organ system involvement may vary between populations including ethnic groups (6). Organ involvement can occur in innumerable combinations and range in severity from mild and readily treatable to organ and/or life-threatening. While SLE is most commonly a relapsing-remitting disease with unpredictable fluctuations in disease activity, persistently active disease or more prolonged periods of remission also occur in some patients (7). It is thus extraordinarily difficult to predict the clinical presentation, time course and disease outcomes in any individual patient.

Just as there is no single diagnostic test for SLE, management is also tailored to the individual according to specific disease manifestations, comorbidities, and patient preferences (8). Non-pharmacological strategies, antimalarials, traditional immunosuppressive drugs and newer biologic agents all have a role in aiming for “remission of disease symptoms, prevention of damage accrual and minimisation of drug side effects, as well as improvement of quality of life” (9). Unfortunately, current therapeutic strategies frequently fall short of achieving these desired treatment goals, and SLE continues to be associated with significant adverse health outcomes, including irreversible organ damage, premature mortality, and reduced health-related quality of life (HRQoL) (10). Understanding and accurately assessing disease activity in SLE is essential to bridging these unmet needs; both clinically to characterise an individual patient's disease status and tailor treatment, and in research to improve our understanding of the efficacy of new treatments and the best way to utilise different therapeutic strategies to optimise patient health outcomes.

Disease activity in SLE

Disease activity refers to inflammatory disease manifestations that are potentially reversible with immunomodulatory treatments. Assessing disease activity is vital due to the association between high disease activity or flare and adverse health outcomes, including irreversible end-organ damage, mortality, and reduced quality of life (11, 12). Conversely, beneficial effects of achieving low disease activity states and remission are well established (13, 14).

Assessing disease activity in SLE is challenging. Activity in SLE can be in a single organ or occur across multiple domains in various combinations, and factors like damage, comorbidities and treatment effects can all confound the assessment of disease activity. Unlike diseases such as hypertension or diabetes where there are biomarkers that allow for direct monitoring of disease status (i.e., blood pressure, or blood glucose levels), in SLE there is no single biomarker that is sufficient for quantifying disease activity. Thus, clinical assessment of disease activity requires a nuanced approach that is individualised based on each unique patient and their disease context. In research, where standardised measurement of disease activity is required, we rely on human-constructed outcome measures to quantify and score disease activity levels and changes over time. Both these approaches will be discussed in the sections below.

Clinical assessment of disease activity

The clinical assessment of disease activity relies on a combination of patient-reported symptoms, physical examination findings, and results of laboratory tests and other investigations, which may vary depending on the individual patient and their specific combination of disease features. Disease activity should be assessed at each clinical visit, with frequency according to clinical need.

Disease activity assessment relies on the clinician evaluating the breadth of inflammatory activity across the vast number of potential manifestations (Table 1), as well as the severity of individual features, which may not be concordant across all affected domains. The history and examination are the foundation of this assessment, screening for symptoms and signs of possible disease activity. More detailed evaluation of identified abnormalities should consider attribution to active SLE (as opposed to other causes), and indicators of severity and impact on the patient. For example, clinical evaluation of joint pain in a patient with SLE would include differentiating inflammatory from non-inflammatory joint pain, examining for joint line tenderness and/or swelling, documenting the number, distribution, and severity of joint involvement, and considering the impact on patient function and quality of life.

Table 1

Table 1. Examples of disease activity across multiple organ domains in SLE.

For some manifestations the history and examination alone may provide sufficient information and clarity about disease activity, but in other cases additional investigations are necessary. Most notably, manifestations such as renal or haematological activity do not always present with overt symptoms but may still be prognostically significant (15, 16). Therefore, routine assessment of disease activity should include a full blood count, renal function, and urinary evaluation for protein (e.g., spot urine protein-creatinine ratio) and sediment. In addition to these organ-based investigations, other laboratory markers of disease activity frequently tested are anti-dsDNA antibody titres (may be elevated in active disease), complements (C3 and/or C4 may be low in active disease) and acute phase reactants (may be elevated in active disease). Anti-dsDNA and complement abnormalities are described in up to 90% of SLE patients, particularly those with lupus nephritis (17, 18). While a rise in anti-dsDNA titre and/or decline in complement levels may predict subsequent disease flares, this is not absolute, and thus is generally not sufficient to escalate treatment (19, 20). Serological abnormalities may also persist despite therapy and clinical remission in a subset of patients (21). Other antibodies associated with SLE, such as ANA or anti-Smith antibodies, while useful for classification and diagnosis, have no role in the monitoring of disease activity. In contrast, acute phase reactants such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) can be helpful but are non-specific in nature. ESR is elevated in up to half of SLE patients and may fluctuate with flares and responses to therapy (22, 23). CRP is less traditionally considered a biomarker of SLE activity, and significant elevations should raise suspicion of concurrent infection, especially if discordant with ESR (24). Increases are nonetheless observed in a significant proportion of patients with active disease, and associations have been identified with serositis and musculoskeletal activity in particular (25).

While some patients present with clear-cut features of disease activity that warrant escalation in immunosuppression, for others, even with a thorough clinical assessment and supporting investigations, the attribution of abnormalities to disease activity can remain uncertain. A common challenge is distinguishing active disease from symptoms and abnormalities of other causes, such as irreversible organ damage, medication effects or concurrent medical issues. Some of the frequently encountered abnormalities detected in SLE patients, examples of causes to consider other than active disease, and potential investigative approaches are outlined in Table 2. It is also important to be aware of common non-inflammatory SLE symptoms, sometimes referred to as “type 2” activity, including fatigue, brain fog, and mood disturbance, which have a marked impact on quality of life but are often discordant with inflammatory symptoms and respond poorly to immunosuppression (26, 27). It is therefore vital to distinguish these symptoms from traditional disease activity to avoid unnecessary immunosuppression and facilitate directed investigation and treatment. Clearly, untangling the multifactorial nature of many SLE features can pose a great challenge, even for experienced clinicians, and it is important to keep an open mind about the aetiology of identified abnormalities, particularly if responses to immunomodulatory treatment are not as expected.

Table 2

Table 2. Examples of how to approach the assessment and attribution of common SLE symptoms and abnormalities to active disease.

The role of disease activity measures

In part due to the complexity of assessing disease activity in SLE, many instruments have been developed to quantify disease activity and facilitate standardised measurement. While many were developed primarily for research purposes, some may also have utility in clinical practice. Notably, recent SLE guidelines suggest using a validated instrument as part of disease activity assessment at each visit (28). As well as providing a measure of disease activity at a particular point in time, the scores generated by a disease activity measure may also be used to define levels of disease activity that have clinical meaning, such as treat-to-target endpoints like low disease activity or remission, or quantify changes in disease activity over time, such as when defining a flare or improvement in response to therapy.

The most common and widely used SLE disease activity measures are summarised in Table 3. This list is not exhaustive, and the sheer number of available measures highlights that no single instrument is fit for all purposes. Most disease activity measures are clinician-reported, as they require judgement of whether to attribute abnormalities to active inflammation. In contrast, patient-reported outcomes are ideally placed to understand symptom burden (including type 2 symptoms) and HRQoL, but are not necessarily specific to disease activity, as they will also capture the effects of factors such as damage, comorbidities, and impact of chronic illness (29).

Table 3

Table 3. Widely used outcome measures for evaluating disease activity and related concepts in SLE, including examples of their typical use in research and clinical settings.

Systemic lupus erythematosus disease activity index (SLEDAI)

The Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) (30) is the most widely used disease activity instrument in SLE. The SLEDAI-2000 (SLEDAI-2K) (31) and Safety of Estrogens in Lupus Erythematosus National Assessment-SLEDAI (SELENA-SLEDAI) (32) are the versions in most common use. The SLEDAI is a composite global disease activity measure consisting of 24 items covering 9 organ systems, of which 16 are clinical and 8 are laboratory variables. Haemolytic anaemia and gastrointestinal lupus are not included. Each item is graded as present or absent, typically based on the preceding 30 days (33). The SLEDAI has weightings for each item between 1 and 8, and the total score is calculated by adding the scores for all items present. This means the same total score can reflect very different patterns of disease activity between patients. Active disease has been defined as a SLEDAI ≥3–4 (34, 35) but higher cut-offs (e.g., SLEDAI ≥6) are typically required for clinical trial entry, and a definition of a high disease activity state has been proposed as SLEDAI-2K ≥10 (36). The SLEDAI has established reliability and validity (37) and predicts important patient outcomes such as damage and mortality (38). It is also simple to use and is feasible in a clinical setting. The most significant limitation is its inability to capture partial improvement or deterioration, or grade severity of a particular manifestation due to the binary nature of scoring (38, 39). For example, presence of any “inflammatory type rash” scores 2 points on the SLEDAI. If the rash were to worsen, or significantly improve but not resolve, the SLEDAI would still score 2 points for rash, even though clinically there has been a change. Caution must therefore be applied when using the SLEDAI to monitor changes in disease activity over time. Another consideration when using the SLEDAI (and other outcome measures incorporating the SLEDAI as a component) is that the measure includes serological markers such as anti-dsDNA and complements, which are not readily accessible in all settings. A modified version of the SLEDAI excluding these serological parameters has previously been reported and validated (37). Although disease activity scores and thresholds using this modified version cannot be considered interchangeable with the original SLEDAI, from a clinical perspective the modified SLEDAI is likely to be sufficient, given it is the clinical features of SLE activity that should primarily inform decision-making.

British isles lupus assessment group (BILAG)

The British Isles Lupus Assessment Group (BILAG) was first developed in 1988 (40) but the 2004 revision (BILAG-2004) (41) is the version in most common use. Unlike the SLEDAI it is not a composite score, but rather a set of organ-based scales grading 9 organ systems from A to E, where A represents major activity, B intermediate activity, C mild activity, D previous involvement but currently inactive, and E no previous activity. These grades are assigned based on an algorithm that integrates 97 disease activity items scored by the clinician as one of not present, improving, the same, worse, or new. Thus, it is a transitional index based on the previous assessment. The BILAG is extremely comprehensive, covering almost all active lupus manifestations. It is well-validated (41), reliable (42) and has superior responsiveness to the SLEDAI (43) despite its use of discrete categories of activity. The main barrier to widespread adoption of the BILAG is feasibility, due to its large number of items, complex scoring algorithm and requirement for formal training for optimal performance (39). The recent development of the Easy-BILAG (44) attempts to address these concerns by offering a more transparent and user-friendly format to improve feasibility and accuracy, whilst maintaining full fidelity to the BILAG-2004. The Easy-BILAG is therefore proposed as the recommended format for scoring the BILAG-2004 index in routine clinical care.

Physician global assessment (PGA)

The Physician Global Assessment (PGA) (45, 46) is a global score of disease activity considering all manifestations, in the opinion of the clinician, assessed on a visual analogue scale. It shows strong concordance with other validated disease activity measures and is sensitive to change, however its reliability is variable (47). This has led to recent efforts to standardise the PGA instrument for use in SLE (48), and the current recommended format is a 0–3 scale where 0 corresponds with no activity, 0.5–1 mild activity and >2–3 severe activity. Typically, the PGA is used in combination with other measures like the SLEDAI to ensure manifestations that are not specifically measured are still captured.

Organ-specific disease activity measures

Traditional SLE disease activity measures such as the SLEDAI and BILAG have focussed on capturing breadth of activity across the heterogeneity and scope of SLE. In contrast, organ-specific measures provide more comprehensive evaluation of a limited set of disease features. This allows for more detailed quantification of activity and change over time. The most common example currently used in SLE is the Cutaneous Lupus Activity and Severity Index (CLASI) which produces a score for mucocutaneous lupus based on items assessing rash, mucosal ulcers, and alopecia (49).

Flare

Measures of flare are predominantly used in research settings. The SELENA-SLEDAI Flare Index (SFI) (50) defines mild/moderate or severe flares based on either an increase in SELENA-SLEDAI score, specific manifestations that are new or worse, defined changes in medications, or an increase in PGA score. It has been shown to perform well for severe flares but is less reliable for mild to moderate flares (51). Concerns about the SFI include outdated medication criteria that do not incorporate newer treatment options or current steroid dosing practices, and contention about how specific manifestations are used to define mild/moderate vs. severe flares. As an alternative, the BILAG can also be used to define flares based on the A-E grading of each organ system. A severe flare is defined as one or more new A grades, a moderate flare as two or more new B grades, and a mild flare as one new B grade (52).

Treat-to-target endpoints

Pre-defined disease activity states such as “remission” and “low disease activity” represent treat-to-target endpoints, whereby therapy is adjusted with the aim of achieving and maintaining a disease state that is associated with clinical benefit. A consensus definition for remission in SLE has been defined by the Definition of Remission in SLE (DORIS) Taskforce, as a clinical SLEDAI-2K = 0, PGA <0.5, and prednisolone ≤5 mg daily with immunosuppression and antimalarials allowed (53). While remission is considered a gold standard treatment target, attainment may not be feasible for many patients (54), and low disease activity represents a less stringent alternative that still confers significant prognostic benefit. The Lupus Low Disease Activity State (LLDAS) is the best validated and most widely adopted of the various low disease activity definitions. LLDAS is defined as SLEDAI-2K ≤4 with no activity in major organ systems, no new lupus activity, PGA ≤1, prednisolone ≤7.5 mg daily and standard maintenance doses of immunosuppression (55). Attainment of LLDAS has been shown to protect against damage accrual, flare, and mortality as well as being associated with improved HRQoL (56–58). While prospective treat-to-target trials are yet to be completed, these target disease activity states have been incorporated into the most recent SLE management guidelines (28) and have been adopted as secondary endpoints in recent SLE clinical trials (59–61).

Clinical trial endpoints: SRI and BICLA

The SLE Responder Index (SRI) (62) and the BILAG-based Composite Lupus Assessment (BICLA) (63) are the most frequently used primary efficacy endpoints in SLE clinical trials. Both the SRI and BICLA combine the SLEDAI, BILAG and PGA assessments. When defining response with the SRI, improvement is determined by the SLEDAI where a reduction of 4 or more points is usually required (the SRI-4). In contrast the BICLA uses the BILAG to define improvement, based on an improvement in all organ systems graded BILAG A and B at the start of the trial. The other two outcome measures (BILAG and PGA for the SRI, and SLEDAI and PGA for the BICLA) ensure concurrent worsening of disease manifestations are not missed by the instrument primarily defining improvement. While these trial endpoints have led to successful drug registrations including belimumab (64) and most recently anifrolumab (65), the SRI and BICLA have well-recognised limitations, and their inconsistent performance across a number of late phase clinical trial programs in SLE are well-documented (66, 67). For example, the SRI and BICLA were developed as adaptations of pre-existing disease activity measures that were not designed for the clinical trial setting, meaning their included items and weightings are not specifically validated for the purpose of defining response in this context (66). They had limited validation prior to widespread adoption, in the absence of suitable alternatives, and can be quite complex and obscure to interpret (66). The reliance on crossing arbitrary binary or discrete thresholds when defining response is particularly problematic. For example, 4 points are scored for arthritis in the SLEDAI-2K, defined as signs of inflammation in 2 or more joints. Thus an SRI-4 response could be achieved if a patient had a joint count that reduced from 2 to 1, which may be of questionable clinical significance. Conversely, a patient whose joint count improved from 20 to 4 would still score 4 points for arthritis on the SLEDAI, and this improvement would not contribute towards being classified as an SRI-4 responder. Such limitations must therefore be considered in the interpretation of clinical trial results based on current efficacy endpoints.

Emerging disease activity measures

Several novel measures of disease activity are also at various stages of development and validation, and although promising, are yet to be widely adopted or replace legacy measures. The SLE Disease Activity Score or SLE-DAS (68) is a global activity score modelled on the DAS-28 used in rheumatoid arthritis. It is a weighted score incorporating 17 items, and several studies have been performed aiming to validate the measure and its scoring thresholds (69–71). The Lupus Foundation of America Rapid Evaluation of Activity in Lupus is another recently developed disease activity measure comprising a set of visual analogue scales rating activity for each major organ system separately (72). It is simple to use, sensitive to change and has a corresponding patient-reported outcome measure that can be deployed alongside the clinician-reported scales (73).

The limitations of current SLE clinical trial endpoints have also led to efforts to develop new approaches to treatment response measurement. The Lupus Multivariable Outcome Score (LuMOS) is a data driven response index developed from the belimumab trial dataset based on six variables including the SELENA-SLEDAI, components of the BILAG, serological markers and prednisolone dose (74). Most recently, the Treatment Response Measure for SLE (TRM-SLE) project has been launched, with a novel outcome measure under development focussing on detailed assessment of activity and response in a select set of domains, specifically tailored for the context of lupus clinical trials (75).

Conclusion

In summary, the clinician impression of overall disease activity in SLE is derived from a comprehensive history and examination supplemented by laboratory and other investigations. This includes identifying what combination of symptoms and other abnormalities represent active inflammation in an individual patient at a particular point in time, characterising their severity and impact, and excluding confounding factors such as damage and comorbidities. Clinical evaluation can be supported by employing validated disease activity measures; however, an understanding of the characteristics and context-specific limitations of different instruments is essential to their appropriate use and interpretation. While assessment of disease activity represents just one component of the broader evaluation and management of patients with SLE, it is essential for directing appropriate clinical decision-making and advancing through research our understanding of the disease and its effective treatment.

Author contributions

AL: Writing – review & editing, Writing – original draft. AW: Writing – review & editing, Writing – original draft. KC: Writing – review & editing, Writing – original draft, Supervision, Conceptualization.

Funding

The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's note

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