Division of Rheumatology, Department of Medicine, Queen Mary Hospital, Hong Kong
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Abstract |
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Methods. One hundred and eighty-six patients with SLE diagnosed between 1992 and 1999 were prospectively followed. Clinical features at presentation, subsequent evolving features, autoantibody profile, damage scores and mortality data were obtained. Prognostic factors for survival were studied by statistical analysis.
Results. One hundred and sixty-three female and 23 male SLE patients were studied. The female to male ratio was 7.1 to 1 and the mean age at presentation was 33.6 yr (range 1275). The mean disease duration was 45.2 months. At diagnosis, arthritis, malar rash and alopecia were the commonest features. During follow-up, the prevalence of nephritis, arthritis, photosensitivity and haematological disease increased significantly. Thirty-one per cent of the patients had organ damage at the time of data analysis and renal disease was the commonest cause. Logistic regression revealed that central nervous system disease, discoid lesions and treatment with high-dose steroid were independent predictors for damage. Nine patients died during the study period (three of disease-related complications and six of infections). The 3-, 5-, and 7-yr survival rates of our cohort were 97, 93 and 93%, respectively. Cox regression analysis revealed that thrombocytopenia and high-dose steroid treatment were independent risk factors for mortality.
Conclusions. The survival of SLE in our southern Chinese patients is similar to that of the Caucasian series reported in the 1990s. Although nephritis contributes to organ damage, it is not a major determinant for survival. Infection remains the commonest cause of death. High-dose steroid treatment and thrombocytopenia are independent risk factors for mortality. Judicious use of immunosuppressive agents is necessary to improve the short-term survival of SLE.
KEY WORDS: Mortality, Outcome, Prognosis, Prognostic indicators, Lupus, Survival.
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Introduction |
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Despite the overall improvement in the survival of patients with SLE, 1025% of patients still succumb within 10 yr of disease onset [9]. Severe organ involvement related to SLE itself [1013] and infection [4, 6, 10, 1416] remain the main causes of early mortality. It has been reported that Asian SLE patients living in the USA and UK have more serious organ manifestations and higher mortality [1719]. Whether this is also related to the poorer socio-economic status of the AsianAmericans remains to be confirmed. However, data regarding survival of SLE in southern Chinese are limited. In a study from Singapore, the causes of 67 deaths of SLE patients over a 4-yr period were described [20]. The actuarial survival rate of their patients was not mentioned and the study population consisted of mixed ethnicity. In an earlier study from our group, the 5- and 10-yr survival rates of 183 patients with biopsy-proven lupus nephritis seen between 1976 and 1997 were reported to be 98.9% and 94.4%, respectively [21]. However, this study did not include patients with renal disease but without histological documentation and those with milder disease with predominant musculoskeletal and dermatological manifestations. Moreover, as the study was conducted retrospectively, selection bias and incompleteness of records were inevitable. In the current study, we prospectively followed a cohort of SLE patients newly diagnosed between 1992 and 1999 in our Lupus Research Clinic in Queen Mary Hospital. Data on mortality, damage and disease manifestations were collected and analysed. Prognostic factors for survival of SLE were studied by both univariate and multivariate models.
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Patients and methods |
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Between January 1992 and March 1999, 186 patients were diagnosed with SLE in the Lupus Clinic. All fulfilled at least four of the American College of Rheumatology (ACR) criteria for the classification of SLE [22] and had their family origin in GuangDong Province, the largest province in the southern part of China. The following information was obtained from all patients at presentation: age, sex, clinical presentation and organ involvement, disease activity scores and autoantibody profile. Patients were followed-up prospectively at regular intervals of 68 weeks. More frequent follow-up was arranged for patients who had severe organ involvement, who had just had a disease flare or who were receiving intensive immunosuppression. Damage scores in each system and mortality data were recorded during the disease course of our patients.
Disease activity was measured by the SLE Disease Activity Index (SLEDAI) [23]. SLEDAI scores were obtained at the time of first presentation and subsequent visits. Assessment of organ damage was made using the Systemic Lupus International Collaborating Clinics/ACR (SLICC/ACR) index [24]. Damage was defined as irreversible impairment that was present after the diagnosis of SLE and persistent for more than 6 months, irrespective of whether it was related to disease activity or treatment. For patients whose SLE was diagnosed before 1997, damage scores were obtained retrospectively. After 1997, the damage index was scored yearly. The total cumulative damage scores were summated for each patient at the end of the study. For patients who died during the follow-up period, the cumulative damage scores just before their death were taken for analysis.
Laboratory evaluation
Antinuclear antibodies (ANA) were determined by indirect immunofluorescence. Anti-dsDNA was assayed using a standard enzyme-linked immunosorbent assay (ELISA) procedure calibrated with an international standard serum (Wo/80). The cut-off point for positivity was set at 154 IU/ml. Anti-extractable nuclear antigen (ENA) antibodies (Ro, La, nRNP and Sm) were studied by counterimmunoelectrophoresis (CIEP). Serum C3 was measured by nephelometry (normal range 60130 mg/dl). Lupus anticoagulant was screened by mixing studies, dilute Russell Venom Viper test, kaolin clotting time and platelet neutralization. Anticardiolipin antibodies (IgG and IgM) were assayed using a standard ELISA kit from Cambridge Life Sciences (Cambridge, UK). A positive test was defined as a value of >10 IU/ml on at least two occasions more than 3 months apart. ANA and anti-ENA were obtained at the time of diagnosis of SLE and were not routinely repeated. Anti-dsDNA and serum C3 levels were assayed during each visit to monitor serological disease activity. Anticardiolipin antibodies and lupus anticoagulant were tested for most patients during the course of the disease at periods of disease activity.
Statistical analysis
Unless otherwise specified, values were expressed as mean ± S.E.M. Comparison between presenting clinical features and the prevalence of various clinical manifestations was made using McNemar's test for matched samples. Correction for multiple significance tests was made by the Bonferroni method. The unpaired Students' t-test was used to compare continuous data between two groups. When normal distribution or equal variance could not be assumed, the MannWhitney U-test was used instead. Correlation study between various continuous data was performed by Spearman's rank correlation test. Univariate and multivariate analysis of the predictive factors for damage were achieved by the chi-square test and logistic regression, respectively and the odds ratios/relative risks were calculated. Estimates of the survival of our patients were studied by life table analysis using the KaplanMeier method. Survival curves with the presence and absence of particular features were compared using the non-parametric log rank test (univariate model). Multivariate analysis of the risk factors for survival was performed using the Cox proportional hazard model. Relative risks and the 95% confidence intervals were calculated for each of the factors studied. Statistical significance was defined as a P-value of less than 0.05, two-tailed.
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Results |
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Regarding immunosuppressive treatment for our cohort of patients, 163 (90%) were treated with corticosteroids, 84 (52%) of whom initially received a high-dose regimen (oral prednisone 1 mg/kg/day or intravenous pulse methylprednisolone therapy) which was mainly indicated for renal, CNS and haematological disease. The cumulative percentages of patients who received hydroxychloroquine, azathioprine and cyclophosphamide were 59, 58 and 26%, respectively.
During follow-up, nine of our patients diedthree of disease-related complications (pulmonary haemorrhage in two and uncontrolled severe pulmonary hypertension in one) and six of infections (nocardial meningitis in one, disseminated cytomegalovirus infection in one, disseminated tuberculosis in one, bronchopneumonia with or without septicaemia in the remaining three). Six other patients developed end-stage renal failure and were dialysed, but none was transplanted. All of these dialysed patients survived. Figure 1 shows the survival and renal survival (survival without dialysis) curves for our cohort of patients. The 3-, 5- and 7-yr survival and renal survival rates were 97, 93, 93%, and 97, 90, 84%, respectively.
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Discussion |
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The overall 5-yr survival rate of our SLE patients was 93%. Because of the problem of recording filing, data regarding the survival of our SLE patients in the 1980s are unavailable for comparison. The survival of our SLE cohort is similar to that of the Caucasian series reported in the 1990s [3, 4, 27]. SLE mortality tends to vary among different geographical areas and ethnic groups. Direct comparison of the survival rates among different studies is not easy because of the discrepancies in patient selection and treatment protocols. Most published survival studies of SLE have been retrospective and selection bias and incompleteness of medical records are major flaws. Moreover, the proportion of patients with severe organ manifestations included in different series as a result of referral pattern may also influence the survival rates. Prospective studies are therefore necessary.
Patients with SLE have an approximately five-fold increased risk of mortality compared with the general population [16]. Many studies have described the causes of death of SLE patients [6, 10, 12, 1416]. Death occurs both early and late in the course of disease and follows a bimodal pattern [12]. Early mortality of SLE is often due to complications related to the active SLE process itself and infection, while vascular events and end organ failure unrelated to active SLE contribute to late mortality [16]. The main causes of death in our patient cohort were infection and active SLE with severe organ involvement, which are consistent with those reported in other series. Because of the relatively short duration of follow-up, long-term survival and causes of late mortality in our cohort have yet to be determined by a longer period of observation.
A number of lupus- and non-lupus-related factors have been described in association with the prognosis of SLE [28]. Major organ manifestations, particularly CNS and renal disease, have long been identified as markers of poor prognosis [29]. Patients who die of active SLE are more likely to have CNS disease [12]. Organic brain syndrome was reported to be a poor prognostic indicator for survival in an early study by Esters and Christian [29]. Moreover, seizure was found to be associated with a poorer overall survival of SLE in a recent study by Ward et al. [9]. Lupus nephritis, especially diffuse proliferative glomerulonephritis, carries a poor prognosis in most studies [4, 8, 9, 27, 3033]. Elevated creatinine, reduced creatinine clearance and progressive WHO class of lupus nephritis were associated with decreased survival. We, however, could not demonstrate either CNS or renal disease to be a significant predictor for survival in our cohort. In fact, all our six patients who developed end-stage renal failure survived with dialysis. Those who died during the study period did not have uraemia. This may reflect that with the availability and improvement in renal replacement therapies, renal disease is no longer a major determinant of survival of SLE. The contribution of CNS disease to survival in our patients is difficult to evaluate because of the relatively small number of patients with CNS manifestations.
Haematological manifestations, in particular thrombocytopenia, have also been cited as adverse factors for poor outcome in SLE [4, 15, 27, 33]. This is in keeping with our findings that thrombocytopenia is a risk factor for mortality in the multivariate model. However, we did not differentiate between the effect of different degrees of thrombocytopenia in our statistical analysis. Apart from those patients who died of pulmonary haemorrhage, which was thought to be caused by fulminant vasculitis, no other patients suffered from significant morbidity and mortality secondary to bleeding complications. The contribution of thrombocytopenia to a poorer survival in our patients could possibly result from its statistical association with nephritis (P = 0.03, chi-square test) and haemolytic anaemia (P < 0.001, chi-square test), which in turn were the main indications for heavy immunosuppressive therapy at the time of diagnosis of SLE.
Treatment is a pivoting factor affecting survival of SLE. Judicious use of steroid and cytotoxic agents such as cyclophosphamide and azathioprine to achieve a better control of disease activity is one of the well-recognized reasons for the improvement in survival of SLE in recent years. However, heavy immunosuppression, such as megadoses of steroid, may adversely affect short-term survival of SLE because of the risk of infection. In the current study we have shown that initial treatment with high-dose oral prednisone or intravenous methylprednisolone bolus is a significant risk factor for damage and mortality in both the univariate and multivariate models. High-dose steroid treatment is associated with a number of side-effects such as susceptibility to opportunistic infection, avascular bone necrosis, cataract, glaucoma, secondary diabetes, osteoporosis and its complications, which contribute significantly to damage and mortality in our cohort. Our result is in keeping with that from Massado et al. [33] who also demonstrated that high-dose steroid for the treatment of patients with more severe disease was associated with higher mortality in their Chilean SLE patients. Given the strong relationship between heavy immunosuppression and organ damage, efforts should assiduously be made to avoid unnecessary over-immunosuppressive treatment in patients with SLE.
Race appears to play a role in disease prognosis in SLE, although it is difficult to separate the effect of race from socio-economic status. Non-White populations residing in Hawaii, which were exclusively Asians, were found to have more serious SLE and mortality than Whites [18]. This may possibly be related to the lower socio-economic condition of the AsianAmericans. Black patients, when compared with Whites, also have more severe organ manifestations and poorer survival [1, 6, 34]. However, a multicentre study of a large cohort of SLE patients demonstrated that apparent racial differences in survival could be accounted for by differences in medical insurance status between Blacks and Whites [32]. Moreover, Ward et al. [35] also showed that socio-economic status, instead of race, is a strong indicator for survival.
The age at onset of SLE has also been reported as a significant predictor for survival, although currently available data are conflicting. In the multicentre study by Ginzler et al. [32], better 1- and 5-yr survival rates were demonstrated in older SLE patients. Moreover, paediatric-onset SLE patients have been associated with a worse prognosis [36]. However, a study comparing the outcome of adult- and childhood-onset SLE patients did not reveal any difference in the 5-yr survival rates [37]. On the contrary, three recent studies showed that increasing age is a risk factor for death [15, 27, 35]. This is in contradiction to the common observation that late-onset SLE often runs a more benign disease course [38, 39] and to our data that older age at disease onset predicts for less renal damage. The effect of gender on SLE survival is also controversial. Male SLE patients were reported to have more severe renal disease and reduced survival [4, 40, 41] when compared with their female counterparts. However, other studies failed to show a gender difference in damage and mortality rates of SLE [27, 42, 43]. We were unable to demonstrate a contribution of either age at onset or sex to survival in our patients. No gender differences in major organ manifestations, damage scores and survival rates could be demonstrated either.
There is still little information in the literature regarding the relationship between damage and survival in SLE patients. In a retrospective study by Stoll et al. [44] that involved an inception cohort of 80 SLE patients, it was reported that the mean renal and pulmonary scores at 1 yr after the diagnosis of SLE predicted for renal failure and mortality, respectively, within 10 yr. Because of the problem of obtaining reliable damage scores retrospectively for some of our patients at 1 yr post-diagnosis of SLE and the small number of patients who developed renal failure (n = 6) or died of cardiopulmonary causes (n = 3) within a relatively short period of follow-up, statistical analysis of our data regarding damage scores at 1 yr and subsequent outcome was not feasible. However, we were unable to demonstrate that the cumulative SLICC score was a predictor for survival in both the univariate and multivariate models.
Although renal damage was the commonest form of organ damage in our cohort and renal disease was a univariate predictor for damage, renal involvement was not an independent predictor for damage in multivariate analysis. This could possibly be explained by the fact that renal disease was associated significantly with other clinical variables such as high-dose steroid treatment (Spearman's rank correlation; rho = 0.39, P < 0.001), which were much stronger determinants for damage. Of the 82 patients with renal disease in our cohort, only 15 (18%) had renal damage. This suggests that most patients with nephritis responded well to treatment and it is therefore not unexpected that renal disease was not shown to be a predictor for renal damage in a separate logistic regression analysis.
In summary, this is the first prospective study of the survival of southern Chinese SLE patients ever reported in the English literature. The short-term survival of our patients is comparable to that of the Caucasian series in the 1990s. Renal disease contributes to organ damage but is no longer a strong determinant for survival. Infection remains the main cause of early death in this cohort. High-dose steroid treatment and thrombocytopenia are independent risk factors for mortality in the multivariate model. Although lupus survival has significantly improved in the recent decade and our data are comparable to others, further improvement should be pursued. Judicious use of corticosteroids and cytotoxic agents to prevent over-immunosuppression, particularly in patients with serious disease manifestations, is essential. Continuous follow-up of our cohort of SLE patients is necessary to accrue data on long-term survival of the disease.
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Notes |
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References |
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