Systemic lupus erythematosus: a clinical update
Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease known for its complexity and heterogeneity. Striking diversity can be observed between individual patients, in terms of clinical manifestations, serological abnormalities, disease progression and response to therapy. Furthermore, dysfunction of a broad range of immune pathways underlies disease development and expression. An appreciation of this diversity is vital in order to diagnose accurately and appropriately treat patients with SLE as there is no one-size-fits-all diagnostic test or treatment. Optimal management involves identifying affected organs, assessing severity, differentiating activity from irreversible damage and tailoring immunosuppressive treatment accordingly. Non-pharmacological interventions, attention to disease and treatment-related comorbidities and addressing the significant impact on health-related quality of life are also crucial to maximising patient outcomes.
Systemic lupus erythematosus (SLE) is a multi-system autoimmune condition, with a prevalence ranging from 4.3 to 45.3 per 100 000 in the Asia Pacific region.1 Approximately 90% of affected individuals are female and among young women SLE is one of the top 10 causes of death.2 The disease is 2–4 times more common, and often more severe, in non-Caucasian individuals, including Asians and Indigenous Australians.3, 4
SLE is most frequently diagnosed between ages 15 and 45. It is a biologically and clinically diverse state, associated with substantial health impact. This is driven by a combination of inflammatory activity in target organs, and treatment-related toxicities, particularly due to glucocorticoids. These factors increase the risk of irreversible organ damage, accumulation of comorbidities and premature death. Ten-year mortality rates in SLE remain around 10%, with the most common causes being organ failure, infection, cardiovascular disease and malignancy.5 SLE is also associated with marked reductions in health-related quality of life, compared not only to the general population, but also other chronic diseases.6, 7
Despite high levels of unmet need, advancing care in SLE has been difficult. Disease complexity and heterogeneity pose significant challenges to understanding the underlying pathophysiology, improving diagnostic and clinical management strategies and tailoring approaches to individual patients. In part arising from this complexity and resulting metrological issues plaguing trials, SLE patients have not benefited from the impact of breakthrough targeted therapies unlike other inflammatory rheumatic diseases. This review will provide a clinically oriented update focussing on SLE diagnosis and management, particularly emphasising the diversity of individual patients and importance of tailored and multifaceted management.
A wide spectrum of immune dysfunction has been described in SLE. Individual patients may have different biological factors underlying their disease development and expression; indeed some consider SLE to be a group of related conditions rather than one disease with a single pathogenesis awaiting discovery.
Genetic and environmental risk factors
Genetic contributions to the risk of SLE are best characterised as polygenic susceptibility, with individual genetic variants only contributing a small amount of excess risk and the presumption that a collection of variants confer risk in individual patients.8, 9 Over 80 individual risk genes have been identified across numerous genome wide association studies in SLE.10 Many of these have clear links to aspects of immunity relevant to disease pathogenesis, such as type 1 interferon production, clearance of self-antigens and the complement pathway. Environmental risk factors implicated in SLE include ultraviolet radiation exposure, smoking, viral infections, low vitamin D and particulate air pollutants.11, 12 A reversible lupus syndrome is also associated with numerous drugs, including tumour necrosis factor inhibitors, isoniazid, hydralazine and minocycline. The precise interactions between different risk factors are complex and their exact roles in disease development are not well understood, particularly when applied at an individual patient level.
The classical hallmark of SLE is the presence of circulating auto-antibodies to nuclear antigens; indeed the most recent classification criteria for SLE (see below) use a positive anti-nuclear antibody (ANA) as the entry point in classification. Combined with this evidence of adaptive immune dysregulation is increasing evidence of innate immune activation, especially type I interferons. Table 1 summarises key immune abnormalities currently implicated in SLE. Many of the dysregulated immune pathways described have or are being investigated as potential treatment targets,10 and given the lack of ideal SLE animal models, human trials of targeted therapies are likely to be most informative on SLE pathogenesis. Despite clinical diversity, the ultimate consequence of immune dysregulation in SLE is a relatively common phenotype of immune-complex mediated direct cell damage and cytokine-driven inflammation affecting a range of organ systems and leading inexorably to irreversible tissue damage. The heterogeneity of immune dysfunction leading to this common phenotype contributes to the clinical complexity of SLE, as well as to the lack of definitive diagnostic and therapeutic biomarkers.
Table 1. Key immune pathways implicated in the pathogenesis of SLE
Abnormalities linked to SLE
Immune clearance mechanisms
Defective clearance of apoptotic debris that triggers innate immune responses and provides a source of nuclear auto-antigens
Type 1 interferon
Key immune pathway implicated in SLE – over half of patients have an ‘interferon signature’ (increased expression of interferon-induced gene transcripts) with multiple pro-autoimmune and pro-inflammatory downstream consequences
Stimulation of innate immunity through formation of neutrophil extracellular traps, as well as mediating tissue damage and stimulating cytokine release
Cytokines and chemokines
Many cytokines and chemokines implicated, with an imbalance between pro-inflammatory and anti-inflammatory cytokine response
Alterations in signalling, proliferation and cytokine production, increased auto-antigen presentation and provision of B-cell help, combined with poorly functional regulatory T-cell responses
Overactive B cells with irregularities in signalling, migration, selection and activation, as well as elevated levels of B-cell stimulating cytokines
Pathogenic autoantibodies cause tissue damage directly and through immune complex formation
- SLE, systemic lupus erythematosus.
Presentation, diagnosis and disease course
While some patients with SLE present with simultaneous classical clinical and immunological findings, for example, a malar rash and inflammatory arthralgias with positive anti-nuclear and anti-double stranded DNA (anti-dsDNA) antibodies, others may have non-specific features, or a stuttering onset over time, making diagnosis more challenging. In the absence of a single causal pathology that can be detected with a laboratory test, initially diagnosing SLE, or attributing new symptoms to SLE in patients with an existing diagnosis, still relies heavily on clinical judgement. The patient demographic, type and combination of clinical features, time course, inflammatory markers, serological findings, histopathology and response to therapy may all form part of this diagnostic process.
SLE has a broad spectrum of potential manifestations that can initially present in virtually any organ system, and with severity ranging from mild to organ or life threatening. Most patients have multi-system involvement, but some can have single-organ dominant disease, for example, isolated lupus nephritis or cutaneous lupus. Various mucocutaneous manifestations (e.g. malar rash, photosensitivity, alopecia, oral ulcers), inflammatory polyarthritis, cytopenias, serositis, glomerulonephritis and constitutional symptoms are the most common disease features. Vasculitis, neurological, cardiac, pulmonary, gastrointestinal and ocular manifestations are also well recognised, but less frequent.
In addition to symptoms directly attributable to immune-mediated inflammation, it is also common for SLE patients to experience symptoms, such as fatigue, myalgias, mood disturbance and cognitive dysfunction. These symptoms do not necessarily correlate with inflammatory activity in other organ systems and typically respond poorly to immunosuppression but can have a debilitating impact on a patient’s quality of life.
The disease course in an individual SLE patient is highly variable. While the classic picture is of a relapsing–remitting pattern of disease with unpredictable flares, some patients experience chronic disease activity,13 while others achieve remission of variable depth and duration.14 Although exceptions abound, in general new disease activity is more likely in the early years after diagnosis and may be less likely in long-standing disease. Regardless of timing, relapses may be characterised by a flare in previously affected organs, new organ systems or a combination of both. It is thus extraordinarily difficult to predict the course of any individual patient.
An important distinction when assessing an SLE patient is to distinguish manifestations attributable to active disease from to those due to established damage. The term disease activity is used to describe immune-mediated inflammation in target organs attributed to SLE, which are potentially reversible with immune-directed therapies. In contrast, damage refers to irreversible changes that arise as a consequence of uncontrolled inflammation (e.g. end-stage kidney disease from lupus nephritis), treatment toxicity (e.g. avascular necrosis from glucocorticoids) or other comorbidities (e.g. malignancy). Accurate attribution of a particular symptom, sign or test abnormality is a common challenge in the assessment of SLE patients. For example, proteinuria may be a marker of renal damage, active nephritis or a combination of both, while leukopenia may be related to disease activity, myelosuppressive medications or infection. Taking into account other clinical features suggesting activity, investigation results and trends over time are required to make a judgement on whether a particular abnormality is related to active disease, and if so, whether this justifies intensification of immunosuppression.
Workup of a patient for whom a diagnosis of SLE is being considered includes both general and organ-specific tests. General tests include antibodies associated with SLE and markers of inflammation. Organ-specific tests help identify which systems are affected, and may include blood and urine tests, imaging and histology. Organ-specific tests are ordered when clinical assessment suggests involvement (e.g. echocardiogram for suspected myopericarditis) or where important involvement may be asymptomatic (e.g. urine assessment for lupus nephritis). A comprehensive history with a systems review covering commonly affected organs, and a thorough physical examination, are therefore vital to guide the appropriate ordering of investigations. An approach to ordering investigations in patients with suspected SLE is outlined in Figure 1. Given SLE often mimics a range of other rheumatological and non-rheumatological conditions, consideration of alternative differential diagnoses should also be undertaken.
An approach to investigations in the diagnosis of systemic lupus erythematosus (SLE). Diagnosis of SLE is assisted by a range of investigations. Some investigations should be performed in all patients with suspected SLE to assist with diagnosis and identify common organ involvement that may present asymptomatically. Other investigations aim to characterise detected abnormalities that may be attributable to SLE. Investigation results must be interpreted in the clinical context, in order to judge whether a patient’s presentation is best explained by SLE or an alternative diagnosis. CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; MRI, magnetic resonance imaging.
Some tests used in SLE have a role purely in diagnosis, while other tests are also helpful in monitoring disease activity and response to therapy. For example, tests used for diagnosis, such as ANA and extractible nuclear antigens (ENA), should not be routinely repeated; indeed, we recently reported extremely low utility of repeating ANA tests when initially negative.15 In contrast, anti-dsDNA antibody titres, C3 and C4 complement levels, inflammatory markers and markers of organ-specific activity (e.g. proteinuria, cytopenia) may fluctuate with disease activity and therefore be serially useful aids to assessment over time. The interpretation of serological tests and inflammatory markers in SLE are discussed in further detail below.
Lupus serology and markers of inflammation
A hallmark immunological feature amongst SLE patients is the production of auto-antibodies to a wide range of nuclear antigens, reflecting the fundamental loss of self-tolerance that is necessary, but not sufficient, to cause disease. Development of measurable autoantibodies may occur years prior to overt clinical disease, usually with more specific lupus antibodies developing closer to the time of disease onset.16
A significant ANA titre is present in almost all SLE patients, and hence is a highly sensitive test. However, specificity is low, and a positive ANA is associated with other autoimmune diseases and occurs in 5–10% of the healthy population.17 The ENA panel identifies the specificity of the antigen against which an ANA is being generated. Common ENA positivity and their frequency in SLE include anti-Ro (25–40%), anti-La (10–20%), anti-Sm (10–30%; with the higher frequency particularly observed in patients with Afro-Caribbean heritage) and anti-ribosomal P (12–16%).18 Anti-Ro/La in pregnant mothers are associated with congenital heart block and neonatal lupus in the foetus, and are hence important to identify in SLE patients planning pregnancy. Anti-Sm is the most specific of the lupus antibodies and is therefore a helpful diagnostic marker when positive. Anti-dsDNA antibodies are also quite specific, particularly in high titres, occur in 50–80% of patients, and often (although not always) vary with disease activity.18 Low concentrations of complement components C3 and C4 are similarly common. Anti-phospholipid antibodies occur in 29–46% of patients with SLE and up to half of these patients may develop arterial and/or venous thrombosis or pregnancy morbidity connoting the clinical state of anti-phospholipid syndrome, although risk varies significantly depending on a range of factors including antiphospholipid antibody type and titre, and concomitant risk factors such as obesity and hypertension.19, 20
General markers of inflammation such as the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are also commonly tested in SLE and are often helpful despite being non-specific. The acute phase response in SLE is characterised by a CRP, which is disproportionately lower than the ESR.21 While modest CRP elevations are often seen in active SLE, high levels (>50–60) are less typical and should prompt exclusion of infection.22
As in many other rheumatic diseases, classification criteria are primarily designed to define inclusion criteria in research studies with a focus on high specificity and homogeneity for research purposes. There are three different classification criteria in current use in SLE; the classical American College of Rheumatology (ACR) criteria, the Systemic Lupus International Collaborating Clinics (SLICC) criteria and most recently the joint European League of Rheumatology Associations (EULAR)/ACR criteria published in 2019. While any of these classification criteria may serve as an aid to remember common manifestations in SLE, they are not a substitute for clinical diagnosis. Instead, the clinical reality of SLE is that it falls on a diagnostic spectrum that cannot be readily defined by any single clinical feature, investigation result or criterion. The key to assessing diagnostically a patient with possible SLE is therefore to identify clinical and laboratory abnormalities that may be consistent with SLE, pursue further investigation to characterise the nature and severity of these abnormalities and any clinically silent but important manifestations (such as glomerulonephritis) and exclude competing differentials. It is then the combination of organs involved, severity of manifestations and symptom impact, which determine both the diagnosis and appropriate management for an individual patient.
Management of SLE
The management of SLE is complex and patients should be managed in a specialised setting, particularly if they have major organ involvement or require immunosuppression. Although there are common themes, treatment is highly tailored to the individual taking into account their combination of clinical features and severity, disease course, comorbidities, tolerance of therapy, fertility considerations and personal preferences. It is vital to consider not only treatment of immune-mediated inflammatory activity, but also managing the broader consequences of the disease and its impact on the patient. Figure 2 provides a visual summary of the overall management approach to patients with SLE. Updated guidelines for the management of SLE and lupus nephritis have also been recently published.23, 24
Management of systemic lupus erythematosus (SLE). A comprehensive approach to SLE management involves both non-pharmacological and pharmacological interventions. While a rheumatologist or organ-specific specialist (e.g. nephrologist, haematologist) usually guides immunosuppression, there are many components of optimal patient management, involving a range of healthcare personnel.
General aspects of management
Although immunosuppression management is typically the domain of the rheumatologist in conjunction with other sub-specialty physicians, there are many additional important facets of management relevant to SLE patients towards which all members of the treating team can make a valuable contribution. These are summarised within Figure 2. Non-pharmacological advice specific to SLE includes avoidance of ultraviolet light and the use of high sun protection factor sunscreen, particularly in patients with cutaneous lupus. More general lifestyle interventions such as smoking cessation may also improve lupus-specific outcomes in addition to usual health benefits.25
Management of cardiovascular disease and associated risk factors warrants particular attention, as SLE patients have markedly higher rates of cardiovascular disease than the general population.26 This increased risk is driven by traditional cardiovascular risk factors, but also by active inflammation and glucocorticoid exposure. In addition to optimising disease control while minimising steroid use, screening and treatment of hyperlipidaemia, hyperglycaemia and hypertension are indicated. Recommendations as per the general population are usually applied, in the absence of disease-specific guidelines.
In addition to cardiovascular disease, infection and malignancy are other common indirect causes of morbidity and mortality in SLE patients. Vaccination status should be reviewed, and influenza and pneumococcal vaccines are recommended in addition to the routine immunisation schedule.27 Live vaccines should be avoided in patients on significant immunosuppression. Attention to age-appropriate malignancy screening, in particular cervical cancer and skin cancer screening, is warranted given associations of SLE and immunosuppression with increased susceptibility.
Bone and musculoskeletal health can be adversely affected in SLE by disease activity, corticosteroid use and lifestyle factors, necessitating attention to modifiable osteoporosis risk factors, bone density screening and in some patients anti-resorptive therapies. Aiming for a vitamin D level between 40 and 100 ng/mL may not only benefit bone health, but also have broader benefits for lupus disease activity.10
As SLE typically affects women of childbearing age, a proactive approach to reproductive health, including contraception, pre-conception counselling and pregnancy management, is vital. Particular issues pertaining to pregnancy in patients with SLE that should be noted include the importance of disease stability, ideally for at least 6 months, on a pregnancy-safe medication regimen (most commonly a combination of hydroxychloroquine, azathioprine and/or steroids) prior to conception. Antibody profile including anti-Ro/La positivity as well as antiphospholipid status should be ascertained early, and additional screening (e.g. for congenital heart block) and management (e.g. anticoagulation) initiated if indicated. Importantly, pregnancy risk and management is highly individual, and early involvement of a multidisciplinary team is recommended. Further information can also be found in recently published comprehensive guidelines addressing reproductive health in SLE.28, 29
Finally it is well recognised that SLE has a major impact on quality of life, including poorer physical, psychological, emotional and social functioning.30 Inevitably contributing factors are many and varied, and factors such as fatigue, comorbid fibromyalgia and depression and anxiety are often significant. Recognition of this impact, addressing readily reversible contributors (e.g. screening for and treating iron deficiency with fatigue) and encouraging patients to engage with a multidisciplinary management team is recommended for these challenging symptoms, as control of disease activity alone is often insufficient.
The vast majority of SLE patients require long-term immune-directed pharmacological therapy to maintain disease control. Complexity arises from the fact that specific manifestations respond differentially to different treatments, and efficacy and tolerability of drugs varies widely between patients. The most commonly prescribed drugs for SLE, their typical use and potential adverse effects are summarised in Table 2. In some cases, non-immunosuppressive pharmacological treatments may also be indicated for specific manifestations, for example, long-term anticoagulation with warfarin in patients with secondary anti-phospholipid syndrome,10 or non-steroidal anti-inflammatory drugs for arthralgia, serositis or fever.
Table 2. Immunosuppressive and immunomodulatory medications used in SLE
Typical indications in SLE
Key adverse effects
Rapid disease control at onset or during acute flare. Long-term use sometimes needed for disease control (target dose ≤7.5 mg)
All patients unless specific contraindications or intolerance
Moderate to severe disease including lupus nephritis
Moderate to severe disease or refractory manifestations especially where safety in pregnancy/breastfeeding required
Skin and joint disease, serositis or other mild–moderate manifestations with inadequate response to hydroxychloroquine
Lupus nephritis – refractory disease or if other agents contraindicated or poorly tolerated
Generally reserved for the most severe or refractory disease including lupus nephritis or neurological involvement
Refractory disease – particularly skin, joints and more recent data in lupus nephritis, particularly if serologically active
Refractory disease – based on evidence of benefit from observational data despite negative phase 3 trials
- GI, gastrointestinal; PML, progressive multifocal leukoencephalopathy; SLE, systemic lupus erythematosus.
Immunomodulatory and immunosuppressive therapies
Anti-malarials (most commonly hydroxychloroquine) are an anchor drug in SLE. They have been shown to reduce disease activity, organ damage, thrombotic complications and mortality31 and hence should be prescribed in the vast majority of SLE patients (usually at doses of 200–400 mg daily). These benefits accrue alongside a favourable toxicity profile, other than the small risk of retinal toxicity with cumulative use that requires ophthalmic screening (annually after 5 years of use, or from 1 year if additional risk factors32) and careful monitoring of dose, with a recent recommendation to lower the ceiling dose from 6.5 to 5 mg/kg/day being challenged by some experts.33
Glucocorticoids are ideally used to gain control of inflammatory activity acutely, such as during disease flares. Low to moderate glucocorticoid doses (e.g. 5–25 mg/day prednisolone or equivalent) are usually sufficient for arthritis, rash and serositis, while severe involvement such as renal, haematological or neurological manifestations often require doses of 0.5–1 mg/kg/day or pulse i.v. methylprednisolone. Topical steroids are an important adjunct in cutaneous disease. As adverse effects of glucocorticoids, which include apparent acceleration of SLE-related organ damage, are dose-dependent,34 treatment guidelines recommend they should be weaned to the lowest possible dose, often requiring concomitant intensification of background immunosuppression to prevent relapse on steroid withdrawal. Unfortunately, as weaning can lead to flare even in stable patients,35 in most large cohorts long-term glucocorticoid use continues in three-quarters of SLE patients.34
Most medications used in addition to anti-malarials and glucocorticoids for SLE act to ameliorate more severe disease activity by non-specific suppression of the immune system. Agents range from milder immunosuppression such as methotrexate (predominantly used for skin and joint disease) to agents including azathioprine, mycophenolate, calcineurin inhibitors and cyclophosphamide for refractory or organ-threatening disease. For example, typical induction therapy for more severe forms of lupus nephritis would entail mycophenolate or low-dose cyclophosphamide for induction of remission, followed by mycophenolate or azathioprine as maintenance.24 A recent prospective trial demonstrated superior outcomes from the use of mycophenolate compared to azathioprine in active non-renal SLE,36 such that this has increasingly been favoured. Prescription and dosing of immunosuppressive medications requires a balance between benefits of optimising disease control while minimising damaging or intolerable side effects.
Unfortunately standard immunosuppressive therapies are often inadequate. Prospective studies of treat-to-target end-points in SLE have shown the benefits of achieving low disease activity or remission states,37 yet for the majority of patients these disease targets are difficult to attain and/or sustain with current therapies. Despite standard therapies, more than half of patients will have periods of active disease over the course of a year,13 rely on chronic glucocorticoids, and accrue damage and morbidity. In those who are refractory or intolerant to usual treatments, there are few alternatives.
Given this significant unmet therapeutic need in SLE, there has been great interest in targeted therapies such as biologic agents. Unfortunately to date failed or negative trials have outnumbered successful trials, at least in part due to the issues of clinical and biological heterogeneity mentioned above, and as a result only one new biologic therapy has been approved for SLE in the last 60 years.38 That drug, the B-cell targeting therapy belimumab,39 is approved for use in Australia but is not Pharmaceutical Benefits Scheme -listed, so its use is limited to specialised centres. Two large phase 3 randomised placebo-controlled trials, and subsequent additional testing have suggested the efficacy of belimumab, with the greatest benefit seen in patients with serological abnormalities and high disease activity.39–41 Importantly, a phase 3 trial recently demonstrated benefit from the addition of belimumab in lupus nephritis,42 and it has recently achieved FDA approval for this indication, a result that may increase its uptake.
Meanwhile, ‘off-label’ use of drugs such as the B-cell depleting agent rituximab remains part of some treatment guidelines, including for lupus nephritis, generally as an add-on therapy in patients with refractory disease. Although the two phase 3 trials of rituximab returned negative,43 issues around study design and the impact of background therapy in particular may have obscured outcomes. There is certainly a large body of non-randomised data from observational studies and registries supporting the efficacy of rituximab in SLE, and the authors, like most lupus clinicians, have observed convincing anecdotal responses to such treatment. Other novel targeted therapies have also shown promise in recent clinical trials, such as the recent positive phase 3 trial of the anti-type I interferon antibody anifrolumab,44 but this awaits a regulatory decision and its place in treatment awaits future strategy trials. Other novel treatment approaches on the horizon include combination rituximab/belimumab and other B-cell targeting approaches, as well as inhibition of janus kinase, bruton tyrosine kinase and co-stimulatory pathways.
SLE is a biologically and clinically complex disease with a significant impact on morbidity, mortality and health-related quality of life. The diagnosis encompasses a broad range of potential manifestations and severity, and making the diagnosis is a nuanced clinical decision. The clinical phenotype of SLE varies widely and immunomodulatory treatment is tailored to specific organ manifestations and severity in the individual, balancing benefits against treatment toxicity. While there is much anticipation around novel targeted therapeutics, optimal management of SLE as a chronic disease extends well beyond immune-directed treatments. Attention to comorbidities, preventative medicine, family planning, overall function and quality of life, and consideration of both pharmacological and non-pharmacological health interventions are important components of management. Thus, all physicians and health practitioners involved in the care of SLE patients have the potential to contribute to improved outcomes and quality of care for this complex patient group.
Fuente: Internal Medicine Journal 51 (2021) 1219–1228 https://doi.org/10.1111/imj.15448