Research ArticleArticle

Differences in Clinical Features and Mortality between Childhood-onset and Adult-onset Systemic Lupus Erythematosus: A Prospective Single-center Study

Young Bin Joo, So-Yeon Park, Soyoung Won and Sang-Cheol Bae
The Journal of Rheumatology August 2016, 43 (8) 1490-1497; DOI: https://doi.org/10.3899/jrheum.151129

Abstract

Objective. To compare clinical features and mortality between childhood-onset systemic lupus erythematosus (cSLE) and adult-onset SLE (aSLE) in a prospective single-center cohort.

Methods. A total of 1112 patients with SLE (133 cSLE and 979 aSLE) were enrolled and followed from 1998 to 2012. The 2 groups were compared regarding American College of Rheumatology (ACR) classification criteria for SLE, autoantibodies, disease activity measured by the Adjusted Mean SLE Disease Activity Index (AMS), damage measured by the Systemic Lupus International Collaborating Clinics/ACR Damage Index (SDI), and medication. The standardized mortality ratio (SMR) was calculated. Predictors of mortality in SLE were evaluated using Cox proportional hazard models.

Results. After a mean followup of 7.6 years, patients with cSLE had a higher number of cumulative ACR criteria and a higher AMS (p < 0.001 each), but there was no difference in SDI (p = 0.797). Immunosuppressants were used more frequently by patients with cSLE (p < 0.001). The SMR of cSLE was 18.8 (95% CI 8.6–35.6), significantly higher than that of aSLE (2.9, 95% CI 2.1–3.9). We found cSLE to be an independent predictor of mortality (HR 3.6, p = 0.008). Moreover, presence of hemolytic anemia (7.2, p = 0.034) and antiphospholipid antibody (aPL; 3.8, p = 0.041) increased the magnitude of risk of early mortality more in the patients with cSLE than in those with aSLE.

Conclusion. The clinical course of cSLE as measured by number of clinical manifestations and disease activity is worse than that of aSLE. Also, cSLE patients with hemolytic anemia and aPL are at greater risk of death than patients with aSLE who have those features.

Key Indexing Terms:

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that predominantly affects women of childbearing age. Patients diagnosed in childhood or adolescence (10%–20%)1 tend to have worse clinical outcomes2,3,4,5,6,7,8,9.

Efforts have been made to compare patients with childhood-onset SLE (cSLE) and adult-onset SLE (aSLE). For example, a nested case-control study was conducted in the LUMINA cohort. However, the information obtained on cSLE was limited because cSLE in that cohort included only adolescent-onset SLE (≥ 11 yrs old)9. Another study was performed in a Canadian cohort, in which patients with cSLE and aSLE received care in the same academic hospital and came from similar social and environmental backgrounds6. However, these patients were in separate pediatric and adult cohorts.

A comparison between patients with cSLE and aSLE in a single cohort with similar backgrounds including environmental, genetic, and ethnic factors and receiving similar treatments is needed, because these factors could substantially affect SLE phenotypes and outcomes. The Hanyang BAE Lupus cohort is a prospective single-center cohort of homogeneous Korean ethnicity in a tertiary academic hospital that has been enrolling patients with cSLE and with aSLE since 1998. The background of this cohort seems to be more homogeneous than other cohorts regarding genetic, ethnic, and treatment factors. Thus, this study should provide more reliable comparisons between cSLE and aSLE without the compounding effects of these factors.

We have for the first time, to our knowledge, compared patients with cSLE versus aSLE from a single ethnic group in a single prospective cohort. Differences in clinical features and outcomes including standardized mortality ratios (SMR) between the 2 groups were investigated and predictors of death were also evaluated.

MATERIALS AND METHODS

Study population

Between February 1998 and December 2012, 1112 patients with SLE were enrolled in the Hanyang BAE Lupus cohort, regardless of age10. This is a prevalent cohort; hence patients with SLE could be enrolled at any point after diagnosis. Patients diagnosed while under the age of 16 were defined as cSLE. All patients were Korean, and informed consent was obtained from all participants. This study protocol was approved by the Institutional Ethics Review Board of Hanyang University Hospital.

Data collection

All data are investigated annually except disease activity, which is evaluated at every clinical visit as well as annually. For data collection, standardized case report forms were used at enrollment and annual followup.

At baseline, the patients’ sex and age at SLE diagnosis were recorded, and they were assessed for clinical manifestations represented by the 1997 American College of Rheumatology (ACR)11 classification criteria, autoantibodies, disease activity measured by the SLE Disease Activity Index-2000 (SLEDAI-2K)12, and organ damage measured by the Systemic Lupus International Collaborating Clinics/ACR SLE Damage Index (SDI)13.

Cumulative results for the ACR criteria, autoantibodies, SLEDAI-2K, SDI, and prescribed medication were also collected. If a new manifestation expressed as an ACR criterion appeared between annual visits, it was recorded in cumulative ACR classification criteria based on medical records, even if it stopped after treatment. The antiphospholipid antibody (aPL) defined the presence of either lupus anticoagulant (LAC) or anticardiolipin antibody (aCL). Thirty patients whose LAC was not examined and for whom the result for aCL was negative were excluded from the estimation of the prevalence of aPL. To measure disease activity, we calculated the Adjusted Mean SLEDAI-2K (AMS), which corresponds to the area under the curve of the SLEDAI-2K scores over time14, because the intervals between patients’ visits could vary. Medications investigated included oral corticosteroid and high-dose intravenous (IV) corticosteroid defined as 500 mg/day or higher of methylprednisolone or hydroxychloroquine, and other immunosuppressants such as cyclophosphamide, mycophenolate mofetil, methotrexate, azathioprine, and cyclosporine.

Estimation of SMR and causes of death

Mortality data were derived by linking with data from the Korean National Statistics Office (KNSO)15, and standardized mortality ratios (SMR) were calculated by comparison with the age- and sex-matched general population from 1998 to 2012, as recorded by the KNSO. Observed deaths were ascertained by linkage of the study patients’ information to data available in the KNSO national death registry, and date and cause of death were identified. The person-years (PY) at risk for each patient were calculated by subtracting the date of enrollment in the cohort from the earlier of 2 exit dates (date of death or the end of the observation period, December 31, 2012). Expected mortality was calculated by multiplying each PY at risk in the cohort by the age- and sex-matched mortality. The SMR was calculated by dividing the observed number of deaths by the expected number, and 95% CI were based on the Poisson distribution.

Statistical analysis

Patient characteristics are expressed by means (SD) or numbers with proportions, as appropriate. Differences between the 2 groups were compared using 2-sample independent t tests, the chi-square test, or Fisher’s exact test.

Cox proportional hazard models were used to assess predictors of mortality.

Two multivariable models were run. Model 1 used cSLE, number of ACR criteria, AMS, SDI score, and anti-Ro antibody as well as baseline age, sex, and disease duration as covariates. To determine whether important SLE manifestations including damage and activity were associated with mortality, we further analyzed those factors using model 2. In model 2, the individual ACR criteria and SDI domains with p < 0.05 in the univariate analysis were entered instead of the mean number of ACR criteria and mean SDI score, and the other covariates were the same as in model 1. To assess the influence of observations in our data on the models, and to check whether any outlier had a disproportionate effect on the models, we carried out model diagnostics using DFBETA analysis, which measures standardized differences between regression coefficients when a given observation is included or excluded. Further, we checked the model assumptions for the Cox proportional hazards model using proportional hazard assumption tests.

All statistical analyses were performed using SAS statistical software (Release 9.1, SAS). A p value < 0.05 was considered statistically significant.

RESULTS

Baseline characteristics

Table 1 lists patient demographic and clinical characteristics. A total of 1112 patients were analyzed, 133 (12.0%) with cSLE and 979 (88.0%) with aSLE. The mean age at the time of diagnosis was 12.5 years (SD 2.4, range 5–15) in the cSLE group and 29.4 years (SD 9.5, range 16–68) in the aSLE group. The female:male ratio in the cSLE group was lower than in the aSLE group (4:1 vs 17:1, cSLE vs aSLE, respectively, p < 0.001).

View this table:
Table 1.

Characteristics of childhood-onset and adult-onset SLE.

Clinical features represented by the ACR classification criteria and autoantibodies

The cumulative number of ACR criteria was significantly higher in the cSLE group than the aSLE group (6.0, SD 1.5 vs 5.5, SD 1.4, respectively, p < 0.001; Table 1). Among the cumulative disease-specific features, significant differences were found for malar rash (p < 0.001), photosensitivity (p = 0.031), renal involvement (p = 0.001), neurologic involvement (p < 0.001), and hemolytic anemia (p = 0.003), which were all seen more often in the cSLE group. Arthritis (p < 0.001) and leukopenia (p = 0.029) were more common in the aSLE group (Supplementary Table 1, available from the authors on request).

In the cSLE group, anti-dsDNA (p = 0.024) and aPL (p < 0.001) were more common than in the aSLE group, and anti-Ro antibody (p = 0.004) was less common (Table 1). In multiple testing using the Bonferroni correction, however, only anti-Ro antibody and LAC were significant.

Medication

The majority of patients were treated with oral corticosteroids. The frequency of immunosuppressant use was higher in the cSLE group (p < 0.001). Among the immunosuppressants, mycophenolate mofetil (39.1% vs 17.3%; p < 0.001) and azathioprine (41.4% vs 29.7%; p = 0.009) were the ones most frequently used during the followup period (Table 1).

Disease activity and organ damage

During the followup period, the cSLE group had a higher maximum SLEDAI score than the aSLE group (p = 0.003), and a higher AMS score (p = 0.001), whereas their cumulative damage was similar, although consisting of different components (Table 2). Of the SDI domains, the frequencies of musculoskeletal damage (p = 0.018) differed between the 2 groups. Of the SDI items, frequencies of cerebrovascular (p = 0.034), seizure (p = 0.004), and proteinuria (p = 0.033) were higher in the cSLE group, whereas erosive arthritis (p = 0.019) was lower.

View this table:
Table 2.

Disease activity and organ damage in childhood-onset and adult-onset SLE.

All-cause SMR and causes of death

Survival rates at 5 and 10 years were 96.5% and 94.0% in the patients with SLE. During 8396.3 person-years of followup, 53 deaths were observed; 9 occurred in the 133 patients with cSLE, and 44 in the 979 with aSLE. The mean age at death in the cSLE group was 21.6 years (range 12–34) and the mean age at cSLE diagnosis was 12.5 years (range 5–15).

Table 3 shows the SMR of patients with cSLE and aSLE, compared to an age- and sex-matched sample of the general population. The overall SMR was significantly higher in the cSLE group (18.75, 95% CI 8.57–35.59) than in the aSLE group (2.89, 95% CI 2.10–3.88). In the aSLE group, subgroup analysis according to age showed that the highest SMR of 11.68 (95% CI 7.40–17.52) was observed in patients of 20–39 years, and this then decreased in patients 40–59 years (2.00, 95% CI 1.09–3.35) and 60–79 years (1.24, 95% CI 0.50–2.55). No effect of age was evident in the cSLE group. Sex did not have any effect on SMR in either group.

View this table:
Table 3.

Standardized mortality ratios (SMR) stratified by age group and sex.

The causes of death in the present cohort were SLE-related diseases (n = 26), infectious disease (n = 11), cerebrovascular disease (n = 4), and malignancy (n = 4; Table 4). Of the 9 deaths in the cSLE group, SLE-related deaths occurred in 6 patients: 1 each for alveolar hemorrhage, autoimmune hepatitis, renal failure, central nervous system (CNS) lupus, bronchiolitis obliterans, and high disease activity without specific organ involvement. The other 3 deaths were due to pneumonia, concomitant Wilson disease, and an accident.

View this table:
Table 4.

Causes of death in childhood-onset and adult-onset SLE.

Predictors of mortality in patients with SLE

To investigate whether cSLE itself increases the risk of death, we performed a Cox regression analysis adjusting for baseline age, sex, disease duration, and other potential predictors. In univariate analysis, during followup these factors were associated with death of patients with SLE (data not shown): cumulative number of ACR criteria (p = 0.045), photosensitivity (p = 0.021), serositis (p < 0.001), neurologic disorder (p < 0.001), thrombocytopenia (p < 0.001), anti-Ro antibody (p = 0.027), AMS (p < 0.001), cumulative SDI score (p < 0.001), presence of cardiovascular damage (p = 0.020), neuropsychiatric damage (p = 0.001), pulmonary damage (p < 0.001), and gastrointestinal (GI) damage (p = 0.002). Because neurologic disorder and neuropsychiatric damage considerably overlap, only neuropsychiatric damage was entered in the multivariable model.

In multivariable model 1, independent predictors of death were cSLE (HR 3.6, p = 0.008), baseline age (1.1, p < 0.001), AMS (1.2, p < 0.001), and SDI score (1.2, p = 0.007). In model 2, independent predictors were cSLE (3.6, p = 0.012), baseline age (1.1, p = 0.001), AMS (1.2, p < 0.001), thrombocytopenia (1.8, p = 0.047), neuropsychiatric damage (2.2, p = 0.041), pulmonary damage (2.9, p = 0.003), and GI damage (3.9, p = 0.039; Table 5). In model assumption tests and outlying and/or influential observations analysis, all variables used in the Cox proportional hazards models satisfied the model assumptions, and there were no potential or effect outliers.

View this table:
Table 5.

Multivariable Cox regression analyses for risk factors of mortality in SLE.

Next, we investigated whether the association between cSLE and death was related to specific features of cSLE compared to aSLE with the same features. The specific features were malar rash, photosensitivity, renal disorder, neurologic disorder, hemolytic anemia, anti-dsDNA, aPL, and cerebrovascular damage, which were more prevalent in cSLE than aSLE. In a Cox regression analysis adjusting for baseline age, sex, disease duration, and AMS, the magnitude of risk was increased in cSLE patients with hemolytic anemia (7.2, p = 0.034) and with aPL (3.8, p = 0.041) relative to an HR of 3.3 for all cSLE (Figure 1). Among the aPL, aCL increased the magnitude of risk to 9.6 (p = 0.009). However, there were no deaths among the patients with cSLE who had LAC. Other features reduced the hazard risk (anti-dsDNA antibody, HR 3.1) or did not differ significantly between cSLE and aSLE.

Figure 1.
Figure 1.

Comparison of mortality between childhood-onset and adult-onset SLE according to the presence of hemolytic anemia and antiphospholipid antibody. Compared to aSLE, the HR of mortality of cSLE was 3.3 greater (95% CI 1.3–8.3, p = 0.013). The magnitude of risk increased in cSLE with hemolytic anemia (HR 7.2, 95% CI 1.2–44.6, p = 0.034) or antiphospholipid antibody (HR 3.8, 95% CI 1.1–13.6, p = 0.041), adjusted for baseline age, sex, disease duration, and AMS. aSLE: adult-onset systemic lupus erythematosus; cSLE: childhood-onset SLE; AMS: adjusted mean Systemic Lupus Erythematosus Disease Activity Index.

DISCUSSION

Age at diagnosis can affect the clinical features and outcomes of SLE16. There has been ongoing interest in differences between cSLE and aSLE. A different sex ratio, genetic factors, hormonal effects, and environmental factors have been suggested as responsible for the differences between the 2 groups. We have compared patients with cSLE and aSLE in a relatively homogeneous cohort and found that the clinical course and outcomes of cSLE are worse than those of aSLE.

Serious clinical manifestations such as renal disorder, neurologic disorder, and hemolytic anemia were significantly more frequent in cSLE compared to aSLE. Malar rash and photosensitivity were also frequent in the cSLE group. These results are consistent with a metaanalysis by Livingston, et al16 except for thrombocytopenia. In our cohort, the frequency of thrombocytopenia was not different in the 2 groups. Consistent with other reports4,5,17,18,19,20, anti-dsDNA antibody was more frequent in cSLE than aSLE. In previous studies considered in a metaanalysis of differences in autoantibody profiles20, the prevalence of anti-dsDNA antibody varied between 49% and 100% and 25% and 84% in cSLE and aSLE, respectively. In our study, the prevalence of anti-dsDNA antibody was 91% in cSLE and 83% in aSLE. The prevalence of aPL was also a little higher than in the previous studies, which ranged from 35% to 44% and 29% to 31% in cSLE and aSLE, respectively8,9. The reasons for this higher prevalence are unclear, but it is likely that our cohort included a greater proportion of severely affected patients with SLE, because our hospital is one of the largest tertiary referral hospitals in Korea.

As outcomes, we compared disease activity and organ damage in the 2 groups. The maximum and cumulative SLEDAI scores were all higher in the cSLE group than the aSLE group. However, the higher disease activity in the cSLE group did not lead to significantly higher cumulative organ damage than in the aSLE group. Some authors have reported that patients with cSLE develop significantly more organ damage than patients with aSLE6,9. However, the SDI score in our cohort was not significantly different between the 2 groups. Our results support the results of the metaanalysis by Livingston and colleagues, which found no significant difference in disease damage between the 2 groups20. Because medication such as corticosteroid can cause organ damage, the similar frequency of high-dose IV corticosteroid given to the 2 groups in our cohort (contrasting with the result of Hersh, et al, showing that patients with cSLE received more IV corticosteroid21) may have led to the similarity in the development of organ damage between our 2 groups. Also, followup for a limited time and loss of patients to followup (8%) may have affected this result, because we compared organ damage according to the domain or item, not the total SDI score. Cerebrovascular damage, seizure, and proteinuria occurred more frequently in the cSLE group. We observed similar patterns to those described in the previous metaanalysis, in which the OR of seizure and proteinuria in cSLE were 2.32 and 1.49, respectively, compared to aSLE16.

The overall SMR of our cohort was 3.37, which is consistent with the results of a metaanalysis22 and a population-based cohort study23. The SMR of the cSLE group was 18.75, significantly higher than that of the aSLE group. The SMR (95% CI) of the cSLE subgroup of those 10–19 years old was 100.00 (20.62–292.24). Two patients with cSLE died at ages 12 and 13, which was rare in the general population. The SMR (95% CI) of the cSLE subgroup of those 20–39 years old was 13.64 (5.00–29.68), similar to results in previous studies. The SMR (95% CI) was reported as 19.2 (14.7–24.7) for those 16–24 years old and 20.4 (9.3–38.7) for those 19–34 years old in the previous studies24,25. These analyses showed that the largest SMR occurred in the cSLE and the lowest in the aSLE. However, this difference should be interpreted with caution in view of the different risks of dying according to age group in the general population, which are lower in the young.

In previous mortality studies of SLE, cardiovascular disease, infection, renal disease, and malignancy were reported to be leading causes of death22,24,26. In our study, SLE-related disease and infection were the major causes of death, followed by cerebrovascular disease and malignancy.

Reports of the causes of death in patients with cSLE are rare. In our present study, SLE-specific diseases, including alveolar hemorrhage, autoimmune hepatitis, renal failure, and CNS lupus, were the main causes of death in the cSLE group. One patient died of uncontrolled pneumonia. The significantly higher disease activity in the cSLE group could have resulted in the higher proportion of deaths associated with SLE-specific diseases. Associated comorbidities and the higher age of the aSLE group could have been the reasons for more infectious disease–associated deaths than in the cSLE group. In a study published in 1987, younger patients more often died of active renal disease and infectious complication than did older patients27. However, that was about 30 years ago. As much as outcomes of patients with SLE have changed and improved, contemporary studies on the cause of death in cSLE are needed.

In our patients with SLE, cSLE was an independent predictor of mortality, as shown in several studies25,28. Neuropsychiatric, pulmonary, and GI damage as well as age at enrollment were also independent predictors of mortality. Moreover, hemolytic anemia and aPL increased the risk of death more in patients with cSLE than in patients with aSLE. In the Hopkins Lupus Cohort study29, hemolytic anemia increased the risk of death. In the LUMINA cohort study30, hemolytic anemia had an effect on increased organ damage, but not on mortality. Because not all studies have enough power to determine predictors of death and organ damage, our study may lack generalizability to other cohorts. Studies also reported aPL to be a risk factor for organ damage, and it was associated with mortality31,32. We do not have a ready explanation for why cSLE with these characteristics carried a higher risk of early mortality than aSLE. However, it could be due to the greater severity of cSLE with these characteristics, and the more extensive use of immunosuppressive agents. Thus, because patients with cSLE had these features as well as neuropsychiatric, pulmonary, and GI damage (predictors of mortality in all patients with SLE), close observation and prompt treatment is needed in these patients to improve survival.

One strength of our study is that differences between cSLE and aSLE were analyzed in a large prospective cohort in a single center enrolling both types of patient. The similar treatments and followup patterns permitted a more accurate comparison of the outcomes. A second strength is the accurate evaluation of SMR, because we obtained information about deaths by linkage with the KNSO and were able to collect all deaths.

A limitation of our study is that our cohort was not an inception cohort. The mean disease duration of our cohort was 3.2 years. This period is not long compared to an inception cohort. The AMS might miss some disease flares or disease status at certain times if patients did not visit our hospital when their disease was active. Also, the conclusions should be interpreted in the context of a potential survival bias, because mortality data were available only over the followup period after enrollment, not from the date of diagnosis.

In this prospective cSLE and aSLE cohort, cumulative clinical features and disease activity were significantly higher in the cSLE than in the aSLE group. Moreover, serious manifestations such as renal disorder, neurologic disorder, and hemolytic anemia were more frequent. Although cumulative organ damage was not significantly different, mortality was higher in the cSLE than in the aSLE group. We found that cSLE was an independent predictor of mortality and the risk of death from SLE was more than 3-fold greater in the cSLE group than in the aSLE group. Also, the risk of death for cSLE was higher in the patients with hemolytic anemia, aPL, and aCL, indicating that close monitoring and careful treatment is needed to prevent death in these patients with cSLE.

Acknowledgment

We are grateful to all the study participants.

  • Accepted for publication April 18, 2016.

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Keywords

SYSTEMIC LUPUS ERYTHEMATOSUS
CHILDHOOD ONSET
CLINICAL FEATURE
MORTALITY

Keywords