Long-Term Prognosis and Causes of Death in Systemic Lupus Erythematosus
Article Outline
Abstract
Purpose
We studied survival rate, prognostic factors, and causes of death in patients with systemic lupus erythematosus (SLE), particularly focusing on the influence of disease severity.
Patients and Methods
A cohort of 207 consecutive Italian patients with SLE were prospectively studied. All prominent clinical and serologic parameters were evaluated and considered as prognostic risk factors. Causes of death were defined on the basis of clinical data and, when available, postmortem examination. Survival was calculated from the time of diagnosis by Kaplan-Meier method.
Results
A total of 17 of 207 patients died; causes of death were active disease manifestations in 35.3% of cases and complication of the disease or its treatment in 64.7% of cases. The survival rates at 5, 10, and 15 years after the diagnosis were 96%, 93% and 76%, respectively. By multivariate analysis of the risk factors, a predictive model consisting of male gender, positive lupus anticoagulant, and “severe” SLE was identified. The survival curve of the patients with severe disease was similar to that of patients with mild disease until 10 to 15 years from the diagnosis. Thereafter the two curves tended to diverge, showing a clear survival decline in patients with severe disease.
Conclusions
Our study confirms the increase of short- and medium-term survival in patients with SLE, but long-term prognosis remains poor in patients with severe SLE manifestations.
Keywords: Systemic lupus erythematosus, Survival, Mortality, Prognosis, Environmental factors, Lupus nephritis, Severe disease
The prognosis of systemic lupus erythematosus (SLE) has improved from less than 50% 5-year survival in 19551 to more than 90% 10-year survival in recent years.2, 3, 4 Several factors could have contributed to the increased survival rate in patients with SLE, including improvement in the classification of the patients, earlier diagnosis, inclusion of milder cases, more intensive schemes of treatment such as the use of cytotoxic/immunosuppressive agents, pulse high-dose prednisone, and advances in the treatment of hypertension, infections, and renal failure, including renal dialysis and transplantation.
The decrease in the mortality caused by active disease manifestations has led to a longer survival of patients with SLE. As a consequence, the causes of death observed in patients with SLE in recent years are different from those reported in the past. Currently, the most frequent causes of death in patients with SLE are infections, acute cardiovascular events caused by atherosclerosis, and cancer.
Recent clinical and experimental studies have indicated that both disease itself and its treatment, especially corticosteroids and immunosuppressants, may play a role in the development of these pathologic processes, although the relevance of these potential contributors in the development of infections,5, 6 atherosclerosis,7, 8, 9, 10, 11 and cancer12 might be different.
It is also noteworthy that severe SLE manifestations, such as glomerulonephritis, neurologic abnormalities, interstitial pneumonitis, and so forth, require more aggressive treatment than mild manifestations and tend to persist longer in an active stage because of the difficulty of inducing their complete remission.13 Therefore, patients with severe manifestations are exposed to higher dosage of corticosteroids and immunosuppressants compared with patients with mild disease.
Most survival studies on SLE have failed to demonstrate a significant contribution to the disease mortality of each severe manifestation itself apart from glomerulonephritis;14 however, the presence of a severe disease as a single contributor has never been evaluated.
The aim of our study was to investigate survival rate, causes of death, and prognostic factors in a cohort of patients with a well-established diagnosis of SLE who were seen at our division during a 40-year period. We especially focused our attention on the contribution of disease severity in patient mortality.
Patients and methods
We recruited 207 consecutive patients with an SLE diagnosis who were seen at the Division of Rheumatology, Padua University, during a 40-year period. A total of 181 patients were female and 26 were male (female:male ratio 7:1). The mean (±standard deviation) age at diagnosis was 32.3
±9 years.
All patients satisfied at least four of the American College of Rheumatology (ACR) criteria for the Classification of SLE15 and were managed according to diagnostic and therapeutic guidelines similar to those reported by ACR in 1999.13 SLE clinical and laboratory parameters, disease activity by European Consensus Lupus Activity Measure score,16 cumulative damage assessed by the Systemic Lupus International Collaborating Clinic and ACR damage index,17 and treatment were evaluated during follow-up.
We used term definitions of SLE-specific features as provided by the ACR criteria.15 Patients were subdivided into two groups: those with mild SLE and those with severe SLE, according to ACR guidelines for referral and management of SLE.14 Briefly, patients with skin, joint, hematologic involvement (apart from hemolytic and aplastic anemia), and serositis were subclassified as having mild SLE, whereas those with major central nervous system manifestations, glomerulonephritis, heart and lung parenchymal manifestations, and hemolytic or aplastic anemia were subclassified as having severe SLE.
Autoantibodies
Antinuclear antibodies and anti–double-stranded DNA antibodies were detected with the indirect immunofluorescence technique by using HEp-2 cells and Crithidia luciliae as a substrate, respectively. Anti-extractable nuclear antigen antibodies (anti-Sm, anti-nRNP, anti-Ro/SSA, anti-La/SSB) were tested by the counterimmunoelectrophoresis technique18, 19 with control sera provided by the Centers for Disease Control (Atlanta, Ga). Lupus anticoagulant (LA) was detected by means of the Russell Viper Venum Time,20 and anticardiolipin antibodies were detected by enzyme-linked immunosorbent assay.21
Survival, Causes of Death, and Prognostic Factors
Patients’ survivals were calculated from the time of the diagnosis.
The causes of death were defined on the basis of clinical data and, when available, postmortem examination. Cause of death was considered to be the pathologic event that primarily contributed to the death.
Risk factors were sex, age at diagnosis, and all prominent clinical and immunologic parameters, including disease treatment.
Statistical Analysis
Programs from the BMDP (La Jolla, Calif) statistical package were used for calculation.22
The univariate analysis of the survival was performed with the Kaplan-Meier method. The time of diagnosis was considered to be the baseline evaluation, and the time of death or the last visit was considered to be the end of follow-up. The Mantel-Cox test was used to compare the survival curves. The multivariate survival analysis was performed with the “Cox-proportional hazard method” evaluating the relative effect of each covariate on the survival function (Score test).
Results
The main clinical manifestations and laboratory abnormalities of 207 patients are summarized in Table 1. Ninety-two patients (44.4 %) had severe SLE, and 115 patients (55.6 %) had mild SLE. At the time of baseline evaluation, the patients had an average European Consensus Lupus Activity Measure score of 3.32±1.26 (range 1-8), and 21 patients (10%) had damage in at least one of the organ systems considered in the Systemic Lupus International Collaborating Clinic and ACR Damage Index.
Table 1. Systemic Lupus Erythematosus Features in 207 Patients with Systemic Lupus Erythematosus: Overall Prevalence and Survival Rates (%) According to Occurrence
| Findings | Overall Prevalence | Survival | |||||
|---|---|---|---|---|---|---|---|
| No. (%) | 5 years | 10 years | 15 years | ||||
| Yes | No | Yes | No | Yes | No | ||
| Arthritis | 156(75.4) | 96 | 97 | 90 | 91 | 75 | 91 |
| Malar rash | 103(49.8) | 98 | 94 | 91 | 90 | 66 | 83 |
| Discoid rash | 25(12.1) | 100 | 96 | 89 | 90 | 89 | 74 |
| Serositis | 49(23.7) | 93 | 97 | 83 | 94 | 72 | 79 |
| Leukopenia | 127(61.3) | 96 | 97 | 92 | 87 | 88 | 65 |
| Thrombocytopenia | 46(22.2) | 91 | 98 | 91 | 89 | 75 | 76 |
| Hemolytic anemia | 25(12.1) | 87 | 97 | 87 | 90 | 44 | 79 |
| CNS involvement | 22(10.5) | 94 | 97 | 86 | 90 | 86 | 73 |
| Renal involvement | 72(34.8) | 98 | 96 | 88 | 92 | 75 | 76 |
| Severe disease | 92(44.4) | 96 | 97 | 85 | 94 | 73 | 72 |
| Anti-dsDNA | 144(69.6) | 97 | 95 | 89 | 92 | 78 | 79 |
| Anti-U1RNP | 43(20.8) | 96 | 96 | 82 | 93 | 75 | 79 |
| Anti-SSA | 61(29.5) | 100 | 95 | 90 | 90 | 90 | 74 |
| Anti-SSB | 26(12.6) | 100 | 96 | 83 | 90 | 83 | 77 |
| Anti-Sm | 34(16.4) | 97 | 96 | 80 | 93 | 68 | 79 |
| aCL | 108(52.4) | 100 | 94 | 89 | 90 | 78 | 74 |
| LA | 32(15.3) | 100 | 96 | 81 | 92 | 54 | 79 |
Survival and Causes of Death
During the observational period, 17 of 207 patients died. The cumulative survivals (Kaplan-Meier) at 5, 10, and 15 years after the diagnosis were 96%, 93%, and 76%, respectively (Fig. 1). The causes of death are reported in Table 2. Sixteen patients (7.7%) were lost to follow-up; their survival was calculated up to the time of dropout.
Figure 1.
Overall survival curve in 207 SLE patients.
Table 2. Causes of Death in 17 Patients with Systemic Lupus Erythematosus
| No. of Patients (%) | Disease Duration at the Time of Death (y) | |
|---|---|---|
| Events caused by active disease manifestations | 6 (35.3) | |
| Renal failure | 1 | 5 |
| Pulmonary hemorrhage | 1 | 1 |
| Pulmonary hypertension | 1 | 3 |
| Intestinal vasculitis | 1 | 5 |
| Aseptic DIC | 2 | 3, 7 |
| Events caused by complications of the disease and/or its treatment | 11 (64.7) | |
| Infections | 4 | 2, 9, 12, 15 |
| Acute cardiovascular events (atherosclerosis) | 2 | 27, 28 |
| Gastrointestinal bleeding | 2 | 7, 12 |
| Cancer | 3 | 15, 21, 40 |
In six patients (35.3% of deaths), the final event was caused by active disease manifestations. End-stage renal failure developed in one male patient despite high-dose corticosteroids and immunosuppressants; he died 1 month after beginning dialysis. A diffuse intravascular coagulation not related to sepsis developed in two patients (a 25-year-old man and a 33-year-old woman). The cause of death was pulmonary hypertension in a 30-year-old man, pulmonary hemorrhage in a 40-year-old woman, and intestinal vasculitis in a 28-year-old woman. This last patient refused immunosuppressive treatment, which was prescribed because of the worsening of the disease.
In 11 patients (64.7%) the final event was a complication of the disease and/or its treatment. Four patients died of infections (23.5% of deaths). In three of these patients the infection occurred after long-standing treatment with high-dose corticosteroids and immunosuppressants. The fourth case was a young female patient who had been recently diagnosed with SLE and treated with high-dose corticosteroids. Another two female patients treated with high-dose corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs) died of massive gastrointestinal bleeding at the ages of 26 and 65 years, respectively.
Three patients died of cancer: a 34-year-old man died of acute megacaryoblastic leukemia; a 36-year-old woman died of a tongue carcinoma (both of whom were treated for a long time with immunosuppressants); and a 74-year-old women with mild SLE associated with Sjögren syndrome, treated with low-dose cortisone and hydroxychloroquine, died of chronic myeloid leukemia. Two patients died of an acute cardiovascular event. A 50-year-old patient died of heart failure after a dialysis session; he had been treated with high-dose corticosteroids, and some years before death osteonecrosis of the right femoral head developed. He refused total hip arthroplasty, and for pain relief he took high doses of NSAIDs, which was the cause of end-stage renal failure leading to dialysis. The second patient was a 61-year-old woman with coronary artery disease and mild SLE who died of myocardial infarction.
Prognostic Factors
The results of the univariate analysis are shown in Table 1. The survival was lower, although not significantly, in patients positive for LA compared with those negative for LA, in patients with severe SLE compared with those with mild SLE (Fig. 2A), and in patients with glomerulonephritis compared with those without renal disease (Fig. 2B).
Figure 2.
Survival in 207 SLE patients. Comparison between patients with severe disease and those with mild disease (A). Comparison between patients with and without glomerulonephritis (B).
The survival rate was significantly lower (P=.03) in men compared with women (Table 3).
Table 3. Survival (%) in 207 Patients with Systemic Lupus Erythematosus by Age and Gender
| Variables | 5 y | 10 y | 15 y | P |
|---|---|---|---|---|
| Age at diagnosis (y) | NS | |||
| 0-15 | 100 | 100 | 100 | |
| 16-49 | 97 | 91 | 76 | |
| ≥50 | 87 | 75 | 75 | |
| Gender | .03 | |||
| Male | 95 | 76 | 38 | |
| Female | 96 | 91 | 81 |
By means of multivariate analysis of risk factors, we identified the best prognostic model for death, which includes male gender, LA positivity, and severe disease (Table 4).
Table 4. Identification of the Best Prognostic Model for Survival by Cox Multivariate Analysis
| B/SE⁎ | χ2 | P | |
|---|---|---|---|
| Male gender | 2.2 | 4.9 | .03 |
| Severe disease | 1.5 | 2.5 | NS |
| Lupus anticoagulant | 0.4 | 0.2 | NS |
⁎B/SE: Standardized partial regression coefficient. |
Discussion
Our study was performed on a cohort of 207 patients followed up for a long period of time. All of the patients satisfied the ACR criteria15 for SLE classification and were managed according to a protocol similar to that recently developed by the ACR.13
The mortality we observed in this cohort was similar to that reported in the most recent studies in which it varied from 6.8% to 20.2% in SLE cohorts followed up for periods ranging from 8 to 14 years.3, 23, 24, 25 The survival rates at 5, 10, and 15 years after the diagnosis were 96%, 93%, and 76%, respectively (Fig. 1), which is similar to that reported in studies published since the middle of the 1990s in industrialized countries3, 25, 26, 27, 28, 29, 30 and confirms the improvement of SLE prognosis in recent years compared with the period from the 1950s to 1980s.31
In our study, one-third of deaths (35.3%) were the result of active disease manifestations (Table 2), including cases with low response to therapy or low compliance. Moreover, patients who died of active disease manifestations were young, with a mean age of 31.2 years. In this regard, we know that corticosteroids and immunosuppressants are able to induce disease remission in the majority of cases. Nevertheless, there is a small percentage of patients who do not respond to treatment. Because SLE is a disease that commonly occurs before the age of 40 years, it is not surprising that the patients who died of active disease manifestations were young.
Therapy with immunosuppressants, corticosteroids, and NSAIDs was associated with severe side effects. We observed infections in four patients and complications resulting from the long use of NSAIDs in two cases. It is worth noting that the majority of the patients (75%) who died of infections had a long-lasting disease and that they had been treated with corticosteroids and immunosuppressants for a long time. Therefore, they were immunocompromised patients with a high risk of infections. The two patients who died of gastrointestinal bleeding had taken cortisone and NSAIDs for a long time, and they were at risk of gastrointestinal bleeding despite correct gastric protection.
The improved survival of patients with SLE, particularly those with severe disease, exposes them to the occurrence of sequelae that can be related in part to the disease itself and in part to its treatment. The most important of these were atherosclerosis and cancer, processes that are not yet completely understood and are still being investigated worldwide.
In our cohort we observed two cases of acute cardiovascular events caused by atherosclerosis, one case of heart failure and one case of myocardial infarction (both in patients with long-lasting disease), and three cases of cancer. Therefore, 11.7% of deaths were attributable to atherosclerosis, and 17.6% of deaths were attributable to cancer.
In patients with SLE, atherosclerosis occurs early in the disease course and is accelerated. Patients with SLE have a higher number of traditional risk factors compared with controls, but it has been clearly shown that traditional risk factors cannot fully explain the higher prevalence of atherosclerosis in patients with SLE.32 During the past few years, the role that corticosteroid therapy plays in the development of clinical and subclinical atherosclerosis has become more evident,7, 8, 9, 10, 11 whereas the role of the disease itself, particularly its activity and/or severity, in the development of atherosclerotic plaques has not been clarified.33, 34
A higher incidence of cancer has been shown in patients with SLE,35 and many authors have suggested that it can be induced by immunosuppressants, especially if they are taken for a long period of time.36, 37 However, the hypothesis that even the disease per se could predispose a person to cancer also has been proposed.38
Among the prognostic factors influencing survival in our study, male gender was associated with a higher mortality (Table 3). This was in keeping with other studies.26, 39, 40 Other important prognostic factors were LA positivity and disease severity (Fig. 2A). Survival tends to be lower in patients positive for LA compared with patients negative for LA, and in patients with severe SLE compared with mild disease.
Renal involvement is by far the most frequent severe manifestation of SLE. It has been shown that renal involvement is a serious prognostic factor, and therefore it is able to affect patient survival.3, 24, 25, 41, 42
By analyzing the curves of patients with severe and mild disease (Fig. 2A), which are similar to those of patients with or without renal involvement (Fig. 2B), we note that the survival curve of patients with mild disease is substantially similar to that of patients with severe disease, but only until 10 to 15 years after the diagnosis. Thereafter the curves tend to diverge, showing a clear survival decline in patients with severe disease.
A possible explanation of this curve variation is that the drugs we use in SLE treatment are effective in controlling even the most severe disease manifestations, including lupus glomerulonephritis, with few exceptions as the result of nonresponsive or noncompliant patients. Their effectiveness is clear at least up to the first 10 to 15 years after the diagnosis, making the survival of patients with severe disease substantially similar to that of patients with mild disease. However, 10 to 15 years after the diagnosis new factors appear that modify the previous profile. These variables could be the result of complex interactions among a number of environmental factors and disease-related factors.
Aggressive therapy has effectively reduced the mortality related to disease activity but also has led to the occurrence of complications that can be related to disease itself or to almost unavoidable drug side effects such as infections, accelerated atherosclerosis, and cancer.
In this respect, severe disease seems to be an important determinant of a poor long-term survival because patients with severe disease are more frequently affected with disease complications and exposed to aggressive treatment. Complications of both disease and treatment probably tend to occur after a number of years after the diagnosis, which may correspond to the 10 to 15 years we observed in our cohort.
Conclusion
Our study confirms the increase of short- and medium-term survival in patients with SLE. The drugs used for the treatment of the severe manifestations of SLE, particularly glomerulonephritis, seem to reduce the overall mortality caused by disease activity during the first 10 to 15 years after the diagnosis, but, unfortunately, they may induce severe side effects leading to a poor long-term prognosis.
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PII: S0002-9343(06)00193-8
doi:10.1016/j.amjmed.2005.11.034
© 2006 Elsevier Inc. All rights reserved.
