Introduction

Systemic lupus erythematosus (SLE) is a chronic, multisystemic autoimmune disease affecting various organs, and principally it can be severe and fatal. However, earlier diagnosis and more appropriate treatment strategies have dramatically improved the 5-year survival rate of patients with SLE from 50% to over 90% over the last several decades, and the 10-year survival rate is also now reported to be nearly 90% [1].

In patients who survive longer than 10 years, the major cause of death has become not simply active SLE itself, and recently the management of SLE has been aimed at not only remission induction and control of the disease activity, but also long-term prevention of chronic organ damage resulting from disease complications and the side effects of treatment. In SLE patients, organ damage has been assessed using the Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology (ACR) Damage Index (SDI) [2, 3]. The score tends to increase over time [4,5,6], and the majority of SLE patients will accrue damage during their clinical course because of many factors such as older age at onset, high disease activity, and long-term adverse events related to medication [5,6,7,8,9,10,11].

Previous studies have revealed that black, Hispanic, and Asian patients have more severe disease expression and a higher disease burden than Caucasians, and show generally lower long-term survival [12,13,14,15]. Most of those studies were conducted in European countries and the USA, and it was pointed out that the generally lower socioeconomic status of these ethnic minorities in the developed countries might have affected their disease course and prognosis. On the other hand, the domestic system for public sharing of medical expenses in Japan has meant that patients can receive the standard therapy equally, regardless of their socioeconomic status.

In this single-centre observational study, we examined the current long-term outcome, causes of death, and factors associated with damage accrual in Japanese patients with SLE.

Patients and methods

This was a retrospective chart study and cross-sectional study of Japanese SLE patients. Figure 1 shows a consort diagram of patient flow through the study. We examined a cohort of 557 patients who had been referred to Niigata University Hospital and diagnosed as having SLE between 1961 and 2013. In this cohort, 99 patients were lost to follow-up during the study period and data from 458 of the patients were successfully obtained. The criteria for the classification of SLE [16, 17] and anti-phospholipid antibody syndrome (APS) [18, 19] were applied and confirmed in 458 patients at the time of the study. Those patients’ clinical statuses including major complications at the latest visit on April 2014 were taken from their clinical records. The average follow-up time per patient was 20 years (2–65 years). For 50 patients who moved to other hospitals during follow-up period, survey forms were sent to the hospitals concerned and the answers were collected from their primary physicians. The study protocol was approved by the ethics committee of Niigata University Hospital and executed in accordance with the Declaration of Helsinki. Survival or correlation analysis that would have affected data on organ damage was not performed for patients who had dropped out at the time of the study.

Fig. 1
figure 1

A consort diagram if of patient flow through the study

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In this cohort, long-term survival rate analysis, survival analysis, and the major complications at the time of the study were examined. The complications such as hypertension, dyslipidemia, and diabetes mellitus were defined as patients who took any medication for each disease at the time of the examination, and osteonecrosis was defined as having a diagnosis by orthopedic surgeons for either X-ray or magnetic resonance imaging during the study period.

For 293 patients who were followed at Niigata university hospital at the time of the study, the SDI was calculated and the correlations between SDI and patients’ clinical data and medications were examined.

Among 115 patients who died during the observation period, the causes of death were also defined on the basis of those data. The causes of death were classified as follows: infections, vascular diseases including sudden death, SLE-related complications, and cancers. SLE-related complications included neuro-psychiatric SLE, hemophagocytic syndrome, thrombotic thrombocytopenic purpura, pulmonary arterial hypertension, and pulmonary hemorrhage associated with SLE, in our study.

Statistical analysis

Statistical analysis was performed using Prism 6 for Mac OS X (GraphPad Software, Inc., San Diego, CA, USA), and StatPlus: mac Pro (AnalystSoft Inc., Walnut, CA, USA). The Kaplan–Meier method was used for survival analysis and the log-rank test for trend for comparison of survival rates. The correlations between SDI and patients’ clinical data were analyzed using Spearman’s correlation coefficient and stepwise multiple regression analysis. A p value of < 0.05 was taken to denote statistical significance.

Results

Long-term survival rate and survival analysis

For the study cohort of 458 patients, the overall 5-, 10-, 20-, 30- and 40-year survival rates were 92.2, 88.4, 77.5, 70.8, and 61.8%, respectively (Fig. 2a).

Fig. 2
figure 2

a The overall long-term survival rate for SLE patients in this study. b Kaplan–Meier survival curves for SLE patients in this study. There were significant improvements in survival rate between groups 2 and 5 (p < 0.0001)

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For patients diagnosed as having SLE before 1970 (group 1, n = 10), between 1970 and 1979 (group 2, n = 57), between 1980 and 1989 (group 3, n = 126), between 1990 and 1999 (group 4, n = 125), and after 2000 (group 5, n = 140), the 5-year survival rates were 71.4, 83.1, 94.5, 93.4, and 96.4%, respectively. There was a significant improvement in survival rate between groups 2–5 (p < 0.0001) (Fig. 2b). In this analysis, we omitted patients in group 1 because the number of patients was very small for examination of statistical significance.

Major complications in the study cohort of SLE patients

Of the 343 patients who were alive at the time of this study, common complications including hypertension (40.8%), dyslipidemia (26.8%), diabetes mellitus (15.7%) and osteonecrosis (11.1%) were observed during the study period (Table 1).

Table 1 Major complications in SLE patients in this study (n = 343)
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Causes of death

Among 115 patients who died during the observation period, the main causes of death were cardiovascular disease (26%), infections (23.4%), SLE-related complications (13%), and cancers (12.1%). In patients who died within 2 years after diagnosis of SLE (n = 34), infections were the predominant cause of death (38.2%), and in those who died between 3 and 10 years after SLE diagnosis (n = 32), vascular disease was the most common cause of death (25%), increasing to 34.6% in patients who died more than 10 years after SLE diagnosis (n = 49). Meanwhile, SLE-related complications still accounted for more than 10% of deaths in patients even at more than 10 years after diagnosis (Fig. 3).

Fig. 3
figure 3

Causes of death in SLE patients in this study

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Multivariate and stepwise multiple regression analyses of factors affecting SDI in the study patients

In this study, we examined the correlations between SDI and the characteristics of the patients who visited Niigata University Hospital at the time of the study (n = 293), including sex, age, daily prednisolone dosage, immunosuppressant administration, bisphosphonate administration, vitamin D administration, serum creatinine levels, serum anti ds-DNA antibody levels, serum CH50 levels, association of APS, and hypertension. Table 2 summarizes the background data of the 293 patients at the time of the study. On the basis of Spearman’s correlation coefficient, the SDI score was positively correlated with serum creatinine levels (r = 0.3812, p < 0.0001), age (r = 0.2963, p < 0.0001), hypertension (r = 0.2299, p < 0.0001), disease duration (r = 0.2052, p = 0.0004), and serum CH50 (r = 0.1339, p = 0.0218), whereas it was negatively correlated with administration of bisphosphonate (r = − 0.115, p = 0.049).

Table 2 Clinical characteristics and laboratory findings in patients who visited Niigata University hospital at the time of the study (n = 293)
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Stepwise multiple regression analysis selected serum creatinine levels (B = 0.6051, p < 0.0001), age (B = 0.0246, p < 0.0001), hypertension (B = 0.3201, p = 0.0031), and antiphospholipid antibody syndrome (B = 0.4837, p = 0.0044), as positive independent variables, whereas administration of bisphosphonate (B = − 0.2636, p = 0.0117) was selected as a negative independent variable (Table 3).

Table 3 Results of stepwise multiple regression analysis of factors affecting SDI in the study patients (n = 293)
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Discussion

It has been well recognized that there are significant differences in how the disease process of SLE affects patients of different racial backgrounds, and similar differences have been demonstrated for disease risk and severity, and treatment responses [5, 6, 11,12,13,14,15]. In general, greater disease severity has been observed clinically in several studies of black, Hispanic, and Asian SLE patients, particularly with regard to renal involvement. The probability of long-term survival in these races has also been reported to be generally lower than in Caucasians.

However, these results need to be interpreted with caution because not only ethnicity, but also socioeconomic status and standards of medical therapies in these patients could affect the outcome of SLE. The recent LUMINA (Lupus in Minorities: Nature vs. Nurture) study, involving one of the biggest prospective cohorts of SLE patients from different racial backgrounds, indicated that Hispanic patients in the USA seemed to have a poorer prognosis than their counterparts from Latin America, despite having a comparable genetic background [20]. Moreover, Gomez-Puerta et al. have recently reported that Asian and Hispanic SLE patients had lower mortality than black, white, and Native American patients enrolled in Medicaid, a healthcare insurance system for the low-income population in USA [21].

SLE has been identified as a specific intractable disease by the Ministry of Health, Labour and Welfare, and a system for public sharing of medical expenses has been established for SLE patients in Japan. Therefore, in Japan, it is possible for all SLE patients to receive uniform treatment regardless of their socioeconomic status.

Our present study indicates that the trends in improvement of long-term survival and changes in major causes of death among SLE patients over more than three decades have shown almost the same patterns as those reported from Europe and USA, where Caucasians represent the major ethnic group. These facts indicate the possible effects of socioeconomic background on disease severity and long-term prognosis, rather than racial or regional differences, in patients with SLE.

Since the probability of long-term survival for SLE patients has been greatly improved, as mentioned above, we need to keep focusing on prevention of complications and organ damage through long-term follow-up. Several factors have already been reported to be associated with higher SDI scores, including older age at SLE onset, racial differences, chronic smoldering disease activity and major SLE disease flares, as well as chronic exposure to glucocorticoid, especially with regard to late-onset damage [5,6,7,8,9,10,11]. The latest study of the Hopkins Lupus Cohort has pointed out many factors associated with damage accrual, including older age, African American ethnicity, lower income, antiphospholipid antibodies, and high disease activity, but the most important predictor of damage progression appeared to be corticosteroid use [5]. The SLICC Inception Cohort study also reported that age, African American ethnicity, SLEDAI-2K score, steroid use, and hypertension were associated with transition from no damage to damage [6].

The present study also revealed that serum creatinine level, older age, complications of hypertension and antiphospholipid antibody syndrome were associated with SDI elevation, supporting the results of previous studies, whereas bisphosphonate administration was associated with a decrease of SDI in SLE patients.

Bisphosphonate has been used as a first-line medication since 2004, according to the Japanese Society for Bone and Mineral Research guidelines for management and treatment of glucocorticoid-induced osteoporosis [22], and 54% of patients in our cohort were administered bisphosphonate. In our study, the daily dosage of glucocorticoid was not related to elevation of SDI. It is still controversial whether long-term use of low-dose glucocorticoid is related to progressive damage accumulation in patients with SLE [5,6,7,8,9,10,11, 23], but appropriate prophylaxis or treatments for steroid-induced adverse events such as hypertension, diabetes, dyslipidemia, and osteoporosis, may be beneficial for prevention of further damage.

Meanwhile, this was a single-center cross-sectional study and the number of patients was somewhat underpowered. Hypertension and kidney dysfunction are well-known factors associated with SDI as we have already mentioned. However, these factors might be the result, and not the cause of the elevation of SDI in our study. For example, patients with hypertension was defined as taking medication at the time of examination in our study, but the detailed information such as their blood pressure control or medical history were not obtained. A further large-scale prospective study will be necessary to examine the significance of these factors in terms of damage accrual in Japanese patients with SLE.

In conclusion, we have demonstrated favorable long-term prognosis and patterns of causes of death in Japanese patients with SLE similar to those reported previously for Caucasian patients. Our study results have also indicated the possible role of SLE disease control as well as long-term management of chronic complications such as hypertension and osteoporosis for prevention of further organ damage in patients with SLE.