Lupus nephritis is associated with more corticosteroid-associated organ damage but less corticosteroid non-associated organ damage

Abstract

Objective

The objective of this study was to investigate the association of lupus nephritis on organ damage and mortality in patients with systemic lupus erythematosus (SLE).

Methods

A total of 1112 patients with SLE were investigated. Lupus nephritis was defined as a proteinuria based on the 1997 American College of Rheumatology criteria. Damage was assessed using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index. The associations of lupus nephritis with overall, non-renal, corticosteroid-associated, and non-associated damage were analyzed using logistic regression. The age-adjusted and sex-adjusted standardized mortality ratio was evaluated in patients with and without lupus nephritis.

Results

The prevalence of lupus nephritis in patients with SLE was 46.3%. Patients with lupus nephritis had a higher percentage of overall cumulative damage than patients without lupus nephritis (51.5% vs. 35.7%, p < 0.001). The odds ratio was 1.40 after adjusting for age at SLE diagnosis, sex, disease duration, anti-malarial agents, immunosuppressive agents and cumulative corticosteroid dose. Among non-renal damage, the odds of corticosteroid-associated damage were higher (2.06, 95% confidence interval (CI) 1.43–2.96) whereas the odds of non-associated damage were lower (0.50, 95% CI 0.35–0.75) in patients with lupus nephritis. The standardized mortality ratios of patients with and without lupus nephritis were 5.17 (95% CI 3.49–7.38) and 2.32 (95% CI 1.47–3.48), respectively.

Conclusion

In patients with SLE, the presence of lupus nephritis is associated with increased corticosteroid-associated damage but less corticosteroid non-associated damage. Also, mortality is significantly higher in patients with lupus nephritis than in those without lupus nephritis.

Keywords

Systemic lupus erythematosus lupus nephritis organ damage corticosteroid

Introduction

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease presenting various clinical manifestations.¹ Some manifestations persist over time and can flare up, causing irreversible organ damage.² Medications used to control the disease manifestations of SLE, including corticosteroids and immunosuppressive agents, are also considered to be major causes of irreversible organ damage.³ Organ damage affects the mortality of patients with SLE, as well as their functioning and health-related quality of life.³ Thus, it is important for clinicians managing patients with SLE to prevent irreversible organ damage.

Lupus nephritis, one of the most serious manifestations of SLE, has been suggested to be a predictor of organ damage accrual.^1,4–6 Also, lupus nephritis is considered a strong determinant for survival.⁵ Since patients with lupus nephritis are more exposed to immunosuppressive agents, such as cyclophosphamide and high-dose corticosteroid, and also have high inflammatory burdens, they might be more vulnerable to organ damage than patients without lupus nephritis. Thus, proper adjustment for these potentially confounding variables needs to be performed to determine the precise effect of lupus nephritis on organ damage. Also, it is important to identify the types of organ damage that are associated with lupus nephritis. However, these aspects have not been previously investigated.

In this study, we investigated the impact of lupus nephritis on organ damage after adjusting for potential confounders. In particular, we identified the types of organ damage that are more associated with lupus nephritis and those that are less associated with lupus nephritis. We also compared the standardized mortality ratios (SMRs) of patients with and without lupus nephritis.

Materials and methods

Study population

Patients enrolled in the Hanyang BAE Lupus cohort from 1998 to 2012 were used in this study. This is a Korean prospective observational cohort for which the clinical information is updated annually, including lupus-associated manifestations, autoantibodies, disease activity, organ damage and medications.⁷ All patients were Korean, and written informed consent was obtained from all participants. This study protocol was approved by the Institutional Ethics Review Board of Hanyang University Hospital.

Data collection

Information was collected on age at SLE diagnosis, sex, disease duration, cumulative burden of disease activity expressed as adjusted mean SLE disease activity index (SLEDAI)-2000 (AMS) score,⁸ organ damage as assessed by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology (ACR) SLE Damage Index (SDI),⁹ and medication ever received. As the SLEDAI score includes features of lupus nephritis, we used the non-renal SLEDAI and non-renal AMS score after excluding urinary casts, hematuria, proteinuria and pyuria instead of total SLEDAI and AMS scores. The cumulative corticosteroid dose of each patient was estimated and converted to an equivalent dose of prednisolone. Total cumulative doses of intravenous corticosteroid >250 mg per day were also calculated.

Definition of phenotypes

Patients who had proteinuria greater than 0.5 g/day or greater than 3+ by dipstick, or cellular casts as represented by the 1997 ACR criteria¹⁰ were classified as patients with lupus nephritis. Patients who had never presented with lupus nephritis were defined as patients without lupus nephritis. According to renal biopsy results, lupus nephritis was further classified into class III/IV and class V. End stage renal disease (ESRD) was defined as less than 15% kidney function (estimated glomerular filtration rate less than 15 ml/min), regardless of dialysis or transplantation.

Organ damage as an outcome

Organ damage at the last follow-up visit was used as an outcome. Both overall organ damage and non-renal organ damage, the latter of which excluded renal damage from SDI domains, were evaluated. Based on minor modifications of the categorization suggested by Gladman et al.,¹¹ non-renal organ damage was further classified according to its association with corticosteroid as follows: corticosteroid-associated damage included cataracts, avascular necrosis, osteoporosis with fracture items, and diabetes. Corticosteroid non-associated damage included five pulmonary damage items (pulmonary hypertension, pulmonary or pleural fibrosis, pulmonary infarction, and shrinking lung), five gastrointestinal damage items (infarction, mesenteric insufficiency, chronic peritonitis, stricture, and chronic pancreatitis), three skin damage items (chronic alopecia, extensive scarring, and skin ulceration), erosive arthritis, premature gonadal failure, and malignancy items. Damage types possibly associated with corticosteroid such as cardiovascular, peripheral vascular and neuropsychiatric damage were excluded from this category.

Mortality as an outcome

Mortality data up to 31 December 2012 were accessed by linkage to data of the Korean National Statistics Office (KNSO).¹² Standardized mortality ratios (SMRs) were calculated by comparison with the general population from 1998 to 2012, as recorded by the KNSO. The person-years at risk for each patient were calculated by subtracting the date of enrollment in the cohort from the earlier of two exit dates (date of death or the end of the observation period, 31 December 2012). Expected mortality was calculated by multiplying each person-year at risk in the cohort by the age-matched and sex-matched mortality.

Statistical analysis

The significance of differences between patients with and without lupus nephritis was examined using the independent Student’s t-test for continuous variables and the chi-square test for categorical variables.

Univariate and multivariable logistic regression analyses were performed to identify factors associated with the development of organ damage, including overall, non-renal, corticosteroid-associated and corticosteroid non-associated damage. All significant factors in univariate logistic analysis were entered into the multivariable logistic regression model. We particularly focused on the effect of lupus nephritis on organ damage in this model.

To calculate the mortality risk of patients with lupus nephritis, the age-adjusted and sex-adjusted SMR and its 95% confidence interval (CI) were estimated. All tests were two-sided, and p values <0.05 were considered to indicate statistical significance. All analyses were conducted using SAS 9.3 statistical software (SAS Institute, Cary, NC, USA).

Results

Comparison of the characteristics of patients with and without lupus nephritis

The characteristics of patients with and without lupus nephritis are reported in Table 1. Of the 1112 patients with SLE, 515 (46.3%) had lupus nephritis. Patients with lupus nephritis were significantly more often male (p = 0.003) and younger at SLE diagnosis (p < 0.001). In addition, patients with lupus nephritis had a longer disease duration from SLE diagnosis to last follow-up (p < 0.001), a higher non-renal AMS score (p < 0.001), a lower percentage of prescribed anti-malarial agents (p < 0.001) and higher percentages of use of corticosteroid (p < 0.001) and immunosuppressive agents (p < 0.001). The cumulative corticosteroid dose was also higher in patients with lupus nephritis than in patients without lupus nephritis (p < 0.001). However, cumulative dose of pulsed intravenous corticosteroid was not different between the two groups (p = 0.947).

Table 1

Demographic and clinical characteristics of patients with systemic lupus erythematosus with and without lupus nephritis (N = 1112).

Characteristics	With LN (n = 515)	Without LN (n = 597)	p
Demographic data
Age at SLE diagnosis, years, mean ± SD	25.2 ± 9.8	29.3 ± 10.7	<0.001
Female sex, n (%)	464 (90.1)	567 (95.0)	0.003
Disease duration, years, mean ± SD	10.0 ± 5.5	8.7 ± 5.5	<0.001
Disease activity
SLEDAI score at enrollment	7.1 ± 4.9	3.9 ± 2.8	<0.001
Non-renal SLEDAI score at enrollment	4.0 ± 3.0	3.5 ± 2.6	0.002
AMS score during follow-up	5.5 ± 2.9	3.3 ± 1.9	<0.001
Non-renal AMS score during follow-up	3.2 ± 1.6	2.6 ± 1.6	<0.001
Medication
Oral corticosteroid, n (%)	509 (98.8)	559 (93.6)	<0.001
Total cumulative dose of corticosteroid, g	27.0 ± 23.0	14.7 ± 14.2	<0.001
First tertile, <9.17, n (%)	107 (20.9)	254 (43.6)	<0.001
Second tertile, ≥9.17, <23.10, n (%)	170 (33.2)	203 (34.8)
Third tertile, ≥23.10, n (%)	235 (45.9)	126 (21.6)
Pulsed intravenous corticosteroid, n (%)	23 (4.5)	18 (3.0)	0.262
Total cumulative dose of pulsed intravenous corticosteroid, g^a	2.2 ± 2.6	2.2 ± 1.5	0.947
Anti-malarial agents, n (%)	450 (87.4)	582 (97.5)	<0.001
Immunosuppressive agents, n (%)	438 (85.1)	329 (55.1)	<0.001
Cyclophosphamide, n (%)	174 (33.8)	24 (4.0)	<0.001
Mycophenolatemofetil, n (%)	200 (38.8)	21 (3.5)	<0.001
Methotrexate, n (%)	83 (16.1)	186 (31.2)	<0.001
Azathioprine, n (%)	237 (46.0)	109 (18.3)	<0.001
Cyclosporine, n (%)	120 (23.3)	83 (13.9)	<0.001
Organ damage
Cumulative SDI, mean ± SD (range)	1.2 ± 1.8 (0–9)	0.6 ± 1.0 (0–9)	<0.001
SDI ≥ 1, n (%)	265 (51.5)	213 (35.7)	<0.001
Renal SDI ≥ 1, n (%)	113 (21.9)

Total cumulative dose of pulsed intravenous corticosteroid was calculated in 41 patients who were treated with pulsed intravenous corticosteroid.

LN: lupus nephritis; SLE: systemic lupus erythematosus; SD: standard deviation; SLEDAI: SLE disease activity index; AMS: adjusted mean SLEDAI; SDI: Systemic Lupus International Collaborating Clinics/ACR SLE Damage Index.

Risk of lupus nephritis for overall organ damage and non-renal organ damage

At the last follow-up, a higher percentage of patients with lupus nephritis had overall cumulative organ damage than did patients without lupus nephritis (51.5% vs. 35.7%, p < 0.001; odds ratio (OR) 1.91) (Table 2). This difference was significant even after adjusting for other potential associated factors identified in univariate analysis, including age at SLE diagnosis, sex, SLE disease duration, anti-malarial agents, immunosuppressive agents and cumulative dose of corticosteroid. The OR of lupus nephritis in our multivariable logistic regression model was 1.40 (95% CI 1.06–1.85) (Table 2). However, lupus nephritis was not associated with non-renal organ damage (p = 0.551) after adjusting for the same potential associated factors (data not shown).

Table 2

Univariate and multivariable logistic regression analyses for organ damage risk.

	Unadjusted		Adjusted^a
	OR (95% CI)	p	OR (95% CI)	p
Age at SLE diagnosis	1.01 (0.996–1.02)	0.189	1.03 (1.01–1.04)	<0.001
Female sex	0.65 (0.41–0.12)	0.058	0.62 (0.38–1.02)	0.057
SLE disease duration	1.13 (1.10–1.16)	<0.001
<5	1.00		1.00
≥5, <15	2.62 (1.92–3.56)	<0.001	1.99 (1.40–2.82)	<0.001
≥15	6.20 (4.11–9.36)	<0.001	4.61 (2.93–7.27)	<0.001
Non-renal AMS score
≤4	1.00
>4, ≤6	0.90 (0.66–1.23)	0.500
>6	1.13 (0.53–2.41)	0.775
Anti-malarial agents	0.53 (0.34–0.84)	0.007	0.51 (0.31–0.84)	0.009
Immunosuppressive agents	2.25 (1.71–2.95)	<0.001	1.57 (1.14–2.15)	0.005
Oral corticosteroid use	2.06 (1.05–4.05)	0.035	–
Cumulative corticosteroid doses
First tertile, <9.17	1.00		1.00
Second tertile, ≥9.17, <23.10	1.48 (1.09–2.01)	0.011	1.10 (0.79–1.54)	0.568
Third tertile, ≥23.10	3.32 (2.44–4.52)	<0.001	1.90 (1.31–2.77)	<0.001
LN
No	1.00		1.00
Yes	1.91 (1.50–2.43)	<0.001	1.40 (1.06–1.85)	0.018

The multivariable logistic model was adjusted for age at SLE diagnosis, female sex, disease duration, anti-malarial agents, immunosuppressive agents, cumulative dose of corticosteroids and LN.

OR: odds ratio; CI: confidence interval; SLE: systemic lupus erythematosus; AMS: adjusted mean SLE disease activity index; LN: lupus nephritis.

Risk of lupus nephritis for corticosteroid-associated and non-associated damage

Corticosteroid-associated damage developed in 17.7% of all patients with SLE. Of the different types of damage, avascular necrosis was the most prevalent (n = 111), followed by cataracts (n = 68), diabetes (n = 21) and osteoporosis with fracture (n = 16) (Figure 1). Corticosteroid non-associated damage developed in 18.3% of all patients with SLE. Of these types of damage, pulmonary damage was the most prevalent (n = 80), followed by deforming or erosive arthritis (n = 47), skin damage (n = 39) and malignancy (n = 33).

A higher percentage of patients with lupus nephritis exhibited corticosteroid-associated damage than of patients without lupus nephritis (22.7% vs. 9.8%, p < 0.001) (Figure 1), but the percentage of patients with lupus nephritis with corticosteroid non-associated damage was lower than that of patients without lupus nephritis (14.8% vs. 21.3%, p = 0.006).

After adjusting for other factors that could potentially affect organ damage, such as age at diagnosis, sex, disease duration, anti-malarial agents, immunosuppressive agents and cumulative dose of corticosteroids, the odds of corticosteroid-associated damage were higher in patients with lupus nephritis than in patients without lupus nephritis (2.06, 95% CI 1.43–2.96). In contrast, the odds for non-associated damage were lower in patients with lupus nephritis than in patients without lupus nephritis (0.50, 95% CI 0.35–0.72) (Table 3). Similar results were obtained when renal biopsy was used to select patients with lupus nephritis (OR 2.38, 95% CI 1.61–3.53 vs. OR 0.45, 95% CI 0.30–0.67, corticosteroid-associated vs. non-associated damage, respectively) (Figure 2). The presence of lupus nephritis class III/IV, but not class V, was also associated with similar risks of developing corticosteroid-associated (OR 2.60, 95% CI 1.73–3.91) and non-associated damage (OR 0.43, 95% CI 0.28–0.67).

Table 3

Risks of corticosteroid-associated and non-associated damage in patients with lupus nephritis compared with those without lupus nephritis.

	Univariate analysis		Multivariable analysis^a
	OR (95% CI)	p	OR (95% CI)	p
Corticosteroid- associated damage	2.90 (2.09–4.02)	<0.001	2.06 (1.43–2.96)	<0.001
Corticosteroid non-associated damage	0.64 (0.47–0.88)	0.005	0.50 (0.35–0.72)	<0.001

The multivariable logistic model was adjusted for age at systemic lupus erythematosus diagnosis, female sex, disease duration, anti-malarial agents, immunosuppressive agents, cumulative dose of corticosteroids, and lupus nephritis.

OR: odds ratio; CI: confidence interval.

Risk of death in lupus nephritis

Among the 1112 patients with SLE, 53 deaths occurred over 8396.3 person-years of follow-up. The age-adjusted and sex-adjusted SMR of all patients with SLE was 3.37 (95% CI 2.53–4.41). Compared with an SMR of 2.32 (95% CI 1.47–3.48) in patients without lupus nephritis, the age-adjusted and sex-adjusted SMR of patients with lupus nephritis was significantly increased, to 5.17 (95% CI 3.49–7.38) (Figure 3).

Stratification according to histologic class revealed that the SMR of class III/IV lupus nephritis was 5.56 (95% CI 3.18–9.03), whereas it was 1.49 (95% CI 0.04–8.32) in patients with class V lupus nephritis. In patients with ESRD, the SMR increased to 9.75 (95% CI 2.66–24.96).

Discussion

Several factors contribute to the development of organ damage in patients with SLE.¹³ Among them, the cumulative inflammatory burden, corticosteroid use, use of immunosuppressive agents such as cyclophosphamide or azathioprine, age and various combinations of these factors could be important factors.^14-17 Patients with damage to major organs accompanied by high inflammatory burdens require treatment with high doses of corticosteroid and immunosuppressive agents. Eventually, these patients are prone to developing organ damage.

In previous studies, lupus nephritis was reported to be an independent predictor of organ damage accrual,^1,4–6 although this association has not been observed in all studies.^18,19 In the present study, lupus nephritis was significantly associated with overall organ damage, while it was not associated with non-renal organ damage. These results are consistent with the idea that renal damage is mostly responsible for the increased development of overall organ damage in patients with lupus nephritis compared with patients without lupus nephritis. However, since non-renal organ damage included 11 domains and 38 items among the SDI categories from which renal damage was excluded, future studies should aim to determine which types of damage are more or less associated with lupus nephritis.

Since the SDI covers many pathologically disparate types of damage, it has been proposed that separate organ damage categories should be defined within the SDI according to their mechanisms. However, studies addressing the mechanisms of organ damage development have been relatively scarce.³ We categorized organ damage into corticosteroid-associated and non-associated damage, and found that lupus nephritis had opposite associations with these two types of organ damage, that is, a positive association with corticosteroid-associated damage and a negative association with non-corticosteroid associated damage.

The categorization used in the present study was based on a report by Gladman et al.¹¹ The authors suggested that organ damage could be categorized by its association with corticosteroid as definitely, possibly, or not at all related to corticosteroid therapy. We selected the definitely and not at all related to corticosteroid therapy groups and defined them as corticosteroid-associated and non-associated damage, respectively. The Systemic Lupus International Collaborating Clinics (SLICC) group have revised the definitions of the damage subgroups of Gladman et al. and categorized cataract, avascular necrosis and osteoporosis as damages definitely related to corticosteroid.²⁰ A recent study from the same group has added diabetes to this subgroup (unpublished). In our data, only the groups with and without avascular necrosis (p = 0.002) and osteoporosis (p = 0.031) had different cumulative corticosteroid doses levels. Thus, these two items of musculoskeletal damage were defined as corticosteroid-associated. In addition, erosive arthritis was classified as non-associated damage because a protective effect of corticosteroid on bone erosion in patients with rheumatoid arthritis has been reported in numerous studies.^21-23 Diabetes was also added to the corticosteroid-associated group.

The positive association of lupus nephritis with corticosteroid-associated damage may be explained by the frequent use of corticosteroid during induction and maintenance periods. Corticosteroid has been clearly established to cause damage in SLE.^15,24–26 One study of the dose effect of corticosteroid on organ damage accrual reported that an increase of 1 mg/day in the mean prednisone dose increased the risk of organ damage by 3%.¹³ However, low-dose corticosteroid has not been shown to result in an increased risk of organ damage.¹⁵ Other studies showed that medium-dose prednisone has a similar efficacy and a better safety profile than higher doses for treating active lupus and lupus nephritis.^24,27 Thus, it is important to reduce the cumulative corticosteroid dose to balance between minimizing organ damage and achieving clinical efficacy in lupus nephritis. However, as other factors associated with corticosteroid-associated damage, such as male gender and longer disease duration, were also significantly increased in patients with lupus nephritis compared with those without lupus nephritis, these factors may also influence the higher frequency of corticosteroid-associated damage in patients with lupus nephritis.

Unlike in patients with lupus nephritis class III/IV, in those with lupus nephritis V a similar pattern of positive association with corticosteroid-associated damage and negative association with non-associated damage was seen, as was presented in Figure 2, but it did not reach statistical significance. The main reason for this is thought to be the small size of the lupus nephritis V group (n = 48). The cumulative corticosteroid dose did not differ between lupus nephritis class III/IV and V. Also other potential clinical features which might affect organ damage did not differ between the two groups.

It is interesting that lupus nephritis is negatively associated with corticosteroid non-associated damage. The precise explanation underlying this observation is unknown. However, extended use of high-dose corticosteroid and immunosuppressive agents in patients with lupus nephritis may lead to reduced corticosteroid non-associated damage by decreasing inflammation and reducing the overall disease activity.

One limitation of our study is that the definitions of corticosteroid-associated and non-associated damage were not validated, although we used only minor modifications of the definitions proposed by Gladman et al. However, a consistent pattern of positive association of lupus nephritis with corticosteroid-associated damage and negative association with corticosteroid non-associated damage was observed when we used different definitions of corticosteroid-associated damage. However, further studies are needed to confirm our conclusion.

Conclusions

Corticosteroid use is a widely known risk factor for the development of organ damage, which is problematic because many patients with lupus nephritis require extended treatment with high dose corticosteroid. Considering these observations, we investigated the association of lupus nephritis with organ damage, in particular corticosteroid-associated versus non-associated damage. Lupus nephritis was associated with overall organ damage. In addition, lupus nephritis was associated with more corticosteroid-associated damage such as avascular necrosis, cataracts, diabetes and osteoporosis with fracture. In contrast, lupus nephritis was associated with less corticosteroid non-associated damage. Regarding mortality, patients with lupus nephritis exhibited a significantly higher SMR compared with patients without lupus nephritis.

Footnotes

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

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