Long-term organ damage

Long-term organ damage and mortality

Systemic lupus erythematosus (SLE) was once regarded as an acute and rapidly fatal condition but better patient care and the advent of novel therapeutic options has led to significant improvements in 5-year survival¹. Nevertheless, rates of premature mortality remain unacceptably high, with leading causes of death including infections, atherosclerotic disease, active SLE and organ damage².

Within a decade of diagnosis, around 50% of patients with SLE develop some form of organ damage³

Accrual of organ damage in SLE often begins early in the disease course and gradually increases as the disease progresses⁴. This irreversible organ damage may be related to disease activity, arising from increased deposition of autoantibodies and immune complexes produced as a result of B cell hyperactivity³. This leads to inflammation and associated microvascular changes that can ultimately compromise organ function³. Disease-related damage is often compounded by further damage caused by comorbid conditions and certain therapeutic agents that are commonly used in the treatment of SLE (Figure 1)^3–5.

Figure 1. Reasons for the development of long-term organ damage in SLE (Adapted^3,6).

The damaging effects of long-term glucocorticoid use for SLE treatment are well established and have become increasingly pertinent as patient survival has improved^3,7

Organ damage in SLE is often measured using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI), which was first developed in 1996⁸. The SDI comprises 41 items used to assess permanent damage across twelve systems including⁸:

• ocular
• neuropsychiatric
• renal
• pulmonary
• cardiovascular
• peripheral vascular
• gastrointestinal
• musculoskeletal
• skin
• endocrine
• gonadal
• malignancies

The SDI measures all damage occurring in patients with SLE, irrespective of cause, as long as it developed after onset of disease and is present for ≥6 months⁹. Scores of ≥1 indicate damage and the SDI has been shown to predict mortality among patients with SLE⁹. In a study carried out on the Hopkins Lupus Cohort, which included over 2,000 patients, SDI score was found to increase at a rate of 0.13 per year¹⁰. A notable finding in this study was the association between glucocorticoid use and damage accrual, which persisted after adjusting for levels of SLE disease activity¹⁰.

The association between long-term organ damage and mortality was recently demonstrated in a UK-based cohort study that included 300 patients with SLE, who were followed for up to 40 years⁵. Of the 300 patients in the study, 87 died during the follow-up period⁵. Rates of organ damage were significantly higher among patients who died during the follow-up period, compared with those who survived (93.1% vs 70.4%, P<0.001)⁵. Similarly, a Chinese study published in 2018 found that risk of mortality was higher among patients with organ damage at baseline, compared with those without organ damage (hazard ratio [HR] 4.299, 95% CI 1.44–12.606, P=0.008; Figure 2)¹¹. Among the 260 patients included in the study, damage most frequently occurred in the musculoskeletal, neuropsychiatric, peripheral vascular and ocular systems¹¹.

Figure 2. Kaplan-Meier survival curves for patients with and without organ damage at baseline (Adapted¹¹). Organ damage is defined as SDI 1. SDI, Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index.

Though the association between organ damage and poor survival is well established, little is known about the extent to which damage contributes to risk of mortality in SLE³. This was addressed in a meta-analysis including 10 different studies from around the globe³. The authors reported a consistent association between organ damage and increased mortality risk, with a 34% increase in mortality risk for every 1-unit increase in SDI (pooled HR: 1.34, 95% CI: 1.24–1.44, P<0.001; Cochrane Q: P=0.027, I² = 52.1%; Figure 3)³.

Figure 3. Hazard ratios for association between organ damage (1-point increase in Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index) and mortality (Adapted³). CI, confidence intervals

Given the relationship between damage accrual and mortality, therapies that prevent or slow organ damage progression are likely to have a favourable impact on mortality¹²

Long-term organ damage drivers and risk factors

Watch the video below for a brief summary of how and why long-term organ damage occurs in patients with systemic lupus erythematosus (SLE) from lupus expert Professor Richard Furie.

Most patients with SLE develop some form of irreversible organ damage over time, but given the relationship between damage and reduced patient survival, it is important to understand what factors contribute to a patient’s overall risk of long-term damage¹³. Understanding which patients are at highest risk of developing long-term organ damage could facilitate more effective intervention and help improve outcomes for patients¹⁴. To date, a number of modifiable and unmodifiable risk factors have been identified, and these are summarised below^13,14.

Anti-phospholipid antibodies and antiphospholipid syndrome

An estimated 20–40% of patients with SLE test positive for antiphospholipid antibodies (aPL), which include lupus anticoagulant, anticardiolipin antibodies and anti-β2-glycoprotein-I. The association between the presence of aPL and organ damage in patients with SLE is well documented and of these patients, over half exhibit characteristics of antiphospholipid syndrome (APS)^5,15,16.

A study published in 2020 reported that aPL positivity was more common among patients with damage than those without (29% vs 11%, P=0.044), though no difference was found between patients who were single-, double- or triple-positive⁵. This concurs with the earlier findings of another group, who reported an association between a clinically significant aPL profile and risk of damage over a 15-year follow-up period¹⁷.

Interestingly, another study also found that patients with SLE-APS tended to have more severe disease and higher rates of major organ involvement than those with either SLE-aPL or SLE¹⁶. This included higher rates of neuropsychiatric, cardiac, pulmonary, renal and ophthalmological manifestations (P<0.001)¹⁶. Patients with SLE-APS also had greater organ damage accrual, with higher Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) scores than other groups (SLE-APS: 1.9 ± 2.2, SLE-aPL: 0.9 ± 1.4, SLE: 1.1 ± 1.6, P<0.001) and mortality rates were significantly higher among patients with SLE-APS (P<0.001)¹⁶.

Age and disease duration

Advancing age is consistently associated with greater organ damage in patients with SLE^5,18. This makes sense given that the SDI can only ever increase over time as it records only irreversible damage⁵. By the same token, a relationship between disease duration and organ damage accrual has also been identified¹⁸.

Advanced age and disease duration are associated with increased risk of organ damage accrual in patients with SLE¹⁸

In 2019, a study carried out on the Italian Early Lupus Project inception cohort found that the number of patients with an SDI of ≥1 grew steadily over the course of 36 months. This study identified a number of different factors that were independently associated with risk of developing organ damage¹⁹. Among these was older age, with patients aged >35 years at diagnosis at significantly higher risk of damage development than those aged <35 years (hazard ratio [HR] 3.0, 95% CI 1.6–5.5, P=0.001)¹⁹. Advanced age at disease onset was also found to be a key predictor of damage in the Hopkins Lupus Cohort¹⁰.

A non-linear relationship between older age and damage in SLE was also observed in the SLICC Inception Cohort, with these effects growing increasingly prominent with advancing age¹³. This can perhaps be attributed to increased sensitivity to the effects of SLE and drug toxicity, given the natural reduction in organ reserve that comes with older age¹³.

Damage also tends to accrue faster in children than in adult patients, with a detrimental effect on prognosis and quality of life^6,20. A study published in 2018 found that the most frequent forms of damage among patients with childhood-onset SLE were cataracts and avascular necrosis, both of which were related to prolonged use of glucocorticoids⁶.

Ethnicity

The impact of ethnicity on damage accrual in SLE has been the subject of some debate. In general, patients of Black, Hispanic or Asian descent appear to have greater disease activity and major organ involvement, and higher rates of damage, compared with Caucasians, though this is not consistent between studies^5,10,21. For instance, results from one study suggest that Asian ethnicity may in fact confer protection against damage, contradicting some other available evidence¹⁴. In addition, while some studies conclude that race and ethnicity have a direct impact on the risk of damage, others suggest that confounding factors may be at play^5,10,21. For example, in 2012, data from the Hopkins Lupus Cohort revealed that although progression was more rapid among African Americans than white patients in a univariate analysis, this did not seem to be the case when a multivariate analysis was carried out¹⁰. Researchers proposed that other variables in the model, such as income, hypertension and proteinuria could be responsible for this observation, as opposed to ethnicity itself¹⁰. Results from a more recent study including 300 British patients concurred with this finding, reporting that differences in damage accrual between ethnic groups was not statistically significant. Further, multivariate analysis did not indicate that ethnicity was responsible for the observed differences between these groups⁵. Interethnic differences in treatment response have also been proposed as a possible explanation for these observations, though further research would be required to confirm this²¹.

Glucocorticoids

Glucocorticoid use is a modifiable risk factor for damage accrual in patients with SL^3,7

The extensive and irreversible adverse effects associated with long-term glucocorticoid use are well established, but their ability to provide rapid relief makes them an attractive therapeutic option for patients with SLE^3,7.

There is a wealth of research supporting the relationship between glucocorticoid use and damage in SLE. For example, data from the Hopkins Lupus cohort revealed that risk of damage was highest among patients taking high doses of glucocorticoids (≥20 mg/day) and was also elevated in those receiving cyclophosphamide¹⁰. A more recent study carried out on 349 patients with SLE found a significant association between chronic damage and glucocorticoid use but not immunosuppressants²².

Despite this seemingly clear association, establishing the proportion of damage attributable to glucocorticoid use is complicated by the fact that these drugs are primarily used to treat patients with active disease¹⁴. Given that higher disease activity has been linked to greater organ damage in SLE, it can be difficult to determine whether changes in SDI arise as a result of the disease itself or the glucocorticoids that are used to treat it¹⁴. Recent efforts to address this uncertainty have found that rates of organ damage accrual affected approximately the same proportion of patients with disease activity as the overall cohort and identified glucocorticoid use as a significant risk factor¹⁴.

There is some evidence to suggest that the risk of irreversible organ damage associated with glucocorticoid use may be dose-dependent, reinforcing current recommendations stating that glucocorticoid dose should not exceed 7.5 mg (prednisone equivalent) and, where possible, these drugs should be withdrawn completely^14,23.

In the following video, Professor Richard Furie offers insight into the love-hate relationship between clinicians and glucocorticoids for the treatment of SLE.

Disease activity and flares

Higher disease activity and flares are closely associated with risk of organ damage accrual in patients with SLE¹⁴. In a recent study, a high disease activity state (HDAS) was defined as reaching a SLEDAI of ≥10 at any point²⁴. This study found that HDAS was associated with an increased likelihood of mild-to-moderate (odds ratio [OR] 17.3, P<0.001) or severe disease flares (OR 14.9, P<0.001). HDAS patients were also more likely to accrue damage (OR 2.3, P=0.003), particularly renal damage (OR 7.2, P=0.001)²⁴. Their chances of exposure to higher cumulative doses of glucocorticoids and immunosuppressants such as mycophenolate mofetil were also significantly increased²⁴.

High disease activity is thought to be associated with greater accrual of damage in SLE, though this may be due to glucocorticoid use^11,24

Interestingly, in a study carried out on the Hopkins Lupus Cohort, the association between disease activity and damage was largely eradicated following adjustment for glucocorticoid use, indicating a potential mediatory role for glucocorticoids in this relationship¹⁰.

Gender

The vast majority of SLE cases are female, with the female:male ratio rising dramatically during reproductive maturity. Interestingly, however, male patients tend to experience more severe disease and poorer survival²⁵.

It is thought that gender also affects the rate of damage accrual, with evidence from larger studies suggesting that men accumulate damage more rapidly women⁵. In one study, which included 1,722 patients with SLE, gender was found to have a significant impact on probability of damage accrual, with men more likely to transition from SDI 0 (no damage) to SDI ≥1 (damage) (relative transition rate 1.48, 95% CI 1.06–2.08)¹³. This was consistent with the findings of an older study, which included 618 patients (63 males) from the Lupus in Minorities: Nature versus Nurture (LUMINA) cohort²⁶. This study found that male gender predicted baseline and was associated with greater damage development, especially during the early stages of disease²⁶.

It is thought that male patients accrue organ damage more rapidly than female patients⁵

Lupus nephritis, in particular, is more common among men than women, and males with lupus nephritis are more likely to experience renal failure than their female counterparts²⁷. 

Previous organ damage

There is strong evidence to suggest that in SLE, damage begets further damage²⁸. In other words, patients who develop early damage are at greater risk of accruing additional damage further down the line^9,13,19. A large study carried out on the SLICC Inception Cohort found that SDI was more likely to increase in patients who had already developed damage prior to enrolment (P<0.001; Figure 4)¹³.

Figure 4. Kaplan-Meier estimate of the survivor function for SDI worsening, stratified by initial SDI state (Adapted¹³). SDI, Systemic Lupus Erythematosus International Collaborating Clinics/American College of Rheumatology Damage Index.

Interestingly, while early damage usually occurs as a result of disease activity, damage that develops later tends to be a consequence of prolonged exposure to drugs such as glucocorticoids²⁰.

Long-term organ damage prevention

Organ damage in systemic lupus erythematosus (SLE) is irreversible and has been associated with an increased mortality risk, making prevention of damage a major priority for patients with this disease^22,29. In order to achieve this, optimisation of disease control is key, and this is reflected in the evolving treat-to-target strategy for patients with SLE³. Similarly, efforts should be made to minimise the impact of comorbidities, and physicians should also strive to reduce drug toxicities wherever possible³. Herein lies the difficulty when it comes to treating patients with SLE: maintenance of a disease-free state often relies on the use of therapies which themselves contribute to long-term damage³⁰.

Controlling disease activity

The relationship between disease activity and organ damage has been studied extensively. For example, analysis of data from the University of Toronto Lupus Cohort revealed that a higher SLE Disease Activity Index 2000 (SLEDAI-2K, an indicator of the clinical burden and effect of active, uncontrolled SLE) score at study entry was predictive of organ damage²⁹. In particular, number of flares is considered an important predictor of organ damage accrual and therefore reducing the frequency of flares may help to improve outcomes for patients³¹.

Maintaining a Lupus Low Disease Activity State (LLDAS) for more than 50% of the time has been associated with a reduced risk of developing irreversible damage in patients with SLE³². LLDAS has therefore emerged as a useful treatment target, which is thought to be achievable in many cases³². In particular, being in LLDAS for more than half of the time has been shown to prevent damage to the musculoskeletal and central nervous systems and the kidneys, as well as osteoporotic fractures and myocardial infarction³². However, current evidence does not suggest that LLDAS prevents cataracts, pulmonary fibrosis, pulmonary hypertension or cognitive impairment³².

Reducing drug toxicity

Though crucial to achieving disease control, several of the agents that are currently used in the management of SLE are themselves associated with an increased risk of organ damage accrual¹⁰.

The role of glucocorticoids, such as prednisone, is particularly well established, and the importance of minimising exposure to these drugs is clearly highlighted in current recommendations²³. Pulse therapy may be used to circumvent some of the issues associated with their long-term use²³. In general, physicians should aim to maintain glucocorticoid dose at ≤7.5 mg/day (prednisone equivalent) where possible²³. Administering high doses of intravenous methylprednisolone may enable patients to receive lower starting doses of oral glucocorticoids and facilitate faster tapering²³. Alternatively, steroid-sparing immunosuppressive agents may be introduced to reduce the need for prolonged glucocorticoid use and help prevent treatment-associated organ damage²³.

Despite the steroid-sparing benefits of immunosuppressive drugs, these agents may equally result in long-term damage to the patient²³. For example, cyclophosphamide has gonadotoxic effects and this agent should be reserved only for cases of organ-threatening disease. Particular care should be taken when treating patients of child-bearing potential²³.

Hydroxychloroquine, which is recommended for all patients with SLE, should also be used with caution, given its association with retinal toxicity²³. Ideally, hydroxychloroquine dose should not exceed 5 mg/kg real body weight and patients should be carefully monitored for signs of ophthalmological damage²³. Nevertheless, hydroxychloroquine is associated with an overall reduction in organ damage, including renal damage, and adherence should therefore be strongly encouraged³³.

There is now also some evidence that treatment with belimumab plus standard of care may reduce the incidence of organ damage accrual³¹. For example, damage accrual was observed in 2.1% of patients following initiation of belimumab therapy in a study investigating various aspects of belimumab use in a real-life setting³¹. A significant difference between mean Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) reported 5 years prior to belimumab initiation and baseline was found (P<0.001), but not between baseline and the end of the follow-up period (P=0.083; Figure 5)³¹. Low levels of organ damage accrual were also reported in a study including patients who had previously completed the BLISS-56 or BLISS-72 trials³⁴.

Figure 5. Damage progression in patients with SLE from 5 years prior to belimumab initiation to end of follow-up period (Adapted³¹). SDI, Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index; SLE lupus erythematosus

Though control of disease activity and reduced exposure to glucocorticoids are currently regarded as the ideal clinical outcomes in SLE, our understanding of the factors that contribute to the development of organ damage is incomplete³². Nevertheless, it is thought that disease-modifying agents and the implementation of steroid-sparing strategies could play an important role in reducing long-term organ damage³.

Minimising comorbidities

In the preclinical stages of SLE, autoantibodies begin to accumulate in the body³⁵. This is followed by the onset of clinical disease. Patients often exhibit a flaring pattern with periods of respite punctuated by spikes in disease activity in which inflammation drives the development of irreversible organ damage³⁵. As the disease progresses, damage is more often treatment-related and the development of comorbidities becomes increasingly burdensome (Figure 6)³⁵.

Figure 6. Clinical course of systemic lupus erythematosus in patients treated using a conventional therapeutic approach (Adapted³⁵). 

SLE is associated with a wide range of comorbidities, many of which contribute to a much-increased risk of early mortality³⁶. Prevention and management of these comorbidities is therefore paramount and modifiable risk factors should be eliminated where possible³⁶. For example, cardiovascular events are the leading cause of death in patients with SLE and so avoidance or management of traditional risk factors such as smoking and obesity is to be encouraged, as should minimisation of glucocorticoid use³⁶. Likewise, vaccinations can be used to help reduce the risk of potentially dangerous infections. Appropriate measures should also be taken to prevent musculoskeletal comorbidities such as osteoporosis³⁶. This could include various lifestyle changes, regular bone density screening and treatment with dehydroepiandosterone (in female patients) and bisphosphonate³⁶.

Managing long-term organ damage in lupus nephritis

Lupus nephritis is a type of glomerulonephritis and represents a major risk factor for morbidity and mortality in systemic lupus erythematosus (SLE)^37,38. It usually develops within 5 years of initial diagnosis and is a common presenting manifestation of SLE³⁸.

In the following video clip, Professor Richard Furie delves into the pharmacological strategies that are currently used in the treatment of lupus nephritis, including insights into what the future might hold.

The potentially devastating impact of lupus nephritis was highlighted by data collected from the Systemic Lupus Erythematosus International Collaborating Clinics (SLICC) inception cohort, which included a total of 1,827 patients with a mean follow-up period of 4.6 years³⁹. Of the total number enrolled in the study, 700 had lupus nephritis. Overall, risk of death was higher among patients with lupus nephritis (hazard ratio [HR] 2.98, 95% confidence intervals [CI] 1.48–5.99, P=0.002)³⁹. Patients who were diagnosed with lupus nephritis were at a greatly increased risk of developing end-stage renal disease (HR 44.7, 95% CI 6.1–329, P=0.001)³⁹. Indeed, there has been little improvement in incidence of end-stage kidney disease among patients with lupus nephritis since the turn of the 21st century⁴⁰.

Factors associated with an increased risk of developing renal involvement include²³:

• male gender
• juvenile onset lupus
• serologically active disease (e.g. anti-C1q antibody positivity)

Patients at high risk should be monitored regularly (≥3 months) for evidence of kidney disease. In patients with suspected lupus nephritis, diagnosis can be confirmed with a kidney biopsy. Lupus nephritis can then be classified according to biopsy histopathology (Table 1)²³.

Table 1. International Society of Nephrology/Renal Pathology Society classification of lupus nephritis (Adapted⁴¹).

As in non-renal lupus, hydroxychloroquine is recommended for all patients with lupus nephritis, except where contraindicated. Various studies suggest that hydroxychloroquine may help decrease the risk of renal flares and end-stage kidney disease, and reduce mortality. A maximum dose of 5 mg/kg real body weight with regular screening for signs of ocular toxicity is recommended³³.

For patients with class III/IV lupus nephritis, mycophenolate mofetil/mycophenolate acid and cyclophosphamide are now recommended as induction therapy. Initial treatment may also involve pulse therapy with high-dose intravenous methylprednisolone, followed by oral prednisone starting at 0.3–0.5 mg/kg/day and reduced to ≤7 mg/day after 3–6 months. High-dose cyclophosphamide may also be considered in certain patient groups³³.

Calcineurin inhibitors have also recently been included in the 2019 update of the European League Against Rheumatism-European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of lupus nephritis, either alone or in combination with mycophenolate mofetil/mycophenolate acid. Though there has been success using a multitarget approach in patients with SLE, the populations studied have thus far been limited to Asia. Drug toxicity remains a challenge and this type of regimen is not recommended in all patient groups³³. The biologic agent belimumab and the calcineurin inhibitor voclosporin received FDA and EMA approval for the treatment of lupus nephritis, following the success of the BLISS-LN (belimumab) and AURA LV phase II/AURORA 1 phase III trials (voclosporin), though their place in the treatment sequence for lupus nephritis is yet to be clarified⁴².

In patients with class V disease, initiation therapy with mycophenolate mofetil/mycophenolate acid, cyclophosphamide or a calcineurin inhibitor (with or without mycophenolate mofetil) are currently recommended³³.

In patients who respond sufficiently well to initiation therapy, maintenance on mycophenolate mofetil/mycophenolate acid or azathioprine is considered an appropriate choice. While patients initially treated with mycophenolate mofetil/mycophenolate acid should continue to be treated with these drugs, cyclophosphamide may be followed by either mycophenolate mofetil/mycophenolate acid or azathioprine. In patients with class V disease, calcineurin inhibitors at the lowest effective dose may be used, keeping in mind their potential adverse effects in the kidneys³³.

Immunosuppressive therapies should not be withdrawn for at least 5–6 years following the initiation of treatment, at which point gradual drug tapering may commence for patients who have achieved a complete renal response ³³.

Off-label rituximab has been used either as an add-on or monotherapy for people with classes III–V disease who have not responded to other treatments³³.

Learn more about treatment options for SLE

Improvements in our ability to treat patients with lupus nephritis mean that fewer patients now develop end-stage kidney disease than in previous years. Nonetheless, some do still develop irreversible kidney damage, requiring kidney replacement therapy. Examples of kidney replacement therapy used in these patients include haemodialysis and continuous peritoneal dialysis. Transplantation remains the preferred option in patients who have achieved inactive renal disease for ≥6 months, as it is associated with considerably better patient survival, compared with other options³³.

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