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Page 1
Systemic lupus erythematosus is a chronic autoimmune
disease that may affect different organ systems and have a
relapsing and remitting course. The broad spectrum of
clinical and immunological expression of SLE has implica-
tions in predicting possible outcomes and determining
adequate treatment.
In the past, SLE was considered a rare and often fatal
disease. Fortunately, it can now be considered, albeit
relatively common, an illness in which mild forms,
prolonged remission periods and long survival may be the
rule [1 3]. On the other hand, as more patients with SLE are
living longer, they also suffer chronic disease-associated
morbidity and/or disability that may herald further illness,
hospitalization and death. Thus, the health care of SLE
patients must include not only disease control and
prevention of mortality but also prevention of morbidity
resulting from the toxic effects of drugs used for often
unnecessarily long periods. Control of acute inflammation
with the most efficacious treatment should be paralleled
with adequate prevention or management of co-morbidity,
without curtailing efforts to reduce and eventually withdraw
all treatment for lupus itself. Appropriate education of
patients, as well as comprehensive psychological and social
support should also be included in the management of SLE.
This review will address the survival rates, prognostic
factors for mortality, causes of death, specific organ damage,
ultimate health status, quality of life, and long-term disease
remission in SLE patients.
Mortality in SLE
Survival rates
The first longitudinal study to estimate survival of SLE
patients was conducted by Merrell and Shulman in the mid
1950s [4], when they reported a survival rate of 51% 4 years
after diagnosis in 99 patients at the Johns Hopkins Hospital.
Recent reports from Europe and North America have
demonstrated that survival rates improved progressively
over time, reaching up to 97% at 5 years and close to 90% at
10 years [5 10]. The life expectancy of patients with SLE at
5 years was found to be similar to that of the general
population of Sweden [5]. In Mexican patients, cumulative
survival rates since the first symptom of SLE were 96 and
92% at 5 and 10 years, respectively [8]. These rates are
similar to those reported by private practice centers in
developed countries that care for considerable numbers of
Hispanic patients [6]. However, studies from other devel-
oping countries reported 10 year survival rates ranging from
50 to 80% [11,12], although a Chilean study showed
improved survival when compared to its own previous
findings [12]. In contrast, a study from India suggests that
survival of SLE patients has not improved in that country
over the past decade [11]. The differences in survival of SLE
patients over time between these two studies could be
related to the economic conditions of their respective
countries.
However, despite local differences, most prognostic
studies have shown marked improvement in the survival
of SLE patients over time, particularly in the last 10 years
[2,3,5 10,12] [Table 1]. Indeed, mortality over a 24 year
period decreased significantly more in SLE patients than in
the general population matched for age and gender [2].
Nonetheless, the mortality in most SLE studies is still
higher than in the general population [2,3].
Explanations for the improved survival of patients with
SLE include earlier diagnosis, recognition of milder cases,
and better therapy. Although no new therapies for SLE were
introduced into general use in the last decade, the improved
survival in SLE may have been influenced by better use of
conventional therapy as well as advances in therapeutic
approaches in general medical care including better
control of infections, hypertension and hyperlipidemia, and
382
C. Drenkard and D. Alarcon-Segovia
IMAJ · Vol 2 · May 2005
The New Prognosis of Systemic Lupus Erythematosus:
Treatment-Free Remission and Decreased Mortality and Morbidity
Cristina Drenkard MD
1
and Donato Alarcón-Segovia MD MS
2
1
Department of Rheumatology, Unit of Internal Medicine, Facultad de Ciencias Médicas, Universidad Nacional de
Córdoba, Argentina;and
2
Instituto Nacional de la Nutrición Salvador Zubirán, and Universidad Nacional Autonoma
de Mexico, Mexico City, Mexico
Key words: systemic lupus erythematosus, antiphospholipid syndrome, disease remission, prognosis, mortality
IMAJ 2005;2:382 387
Reviews
______________________________
SLE = systemic lupus erythematosus
Table 1. Survival rates in SLE patients from different American
and European countries, 1991 1999
______________________________________________________________
Country City
Year
Survival rates (%) Study (Ref.)
5 yr
10 yr
______________________________________________________________
USA
Los Angeles
1991
97
93
Pistiner et al. [6]
USA
Stanford
1991
96
89
Seleznick et al. [7]
Mexico
Mexico City
1994
96
92
Drenkard et al. [8]
Chile
Santiago
1994
87
79
Massardo et al. [12]
Canada
Toronto
1995
93
85
Abu-Shakra et al. [9]
Europe
Multicenter
1999
95
Cervera et al. [10]
______________________________________________________________
Page 2
use of renal dialysis and transplantation [2,3]. Differences in
patterns of treatment over time were observed in the
Rochester study, with increased use of antimalarials and
lesser use of cyclophosphamide and corticosteroids in 1980
1992 compared to1950 1979 [3]. Although this finding could
be attributed to less severe disease in patients who were
more recently diagnosed, it is more likely to reflect changing
patterns of practice.
Major prognostic factors for mortality
· Social and demographic factors
Factors such as age at onset, gender, race and socioeconomic
status are implicated in the prognosis of patients with SLE.
Their contribution as predictors of mortality, however, is
controversial and its interpretation difficult. It may depend
on several variables, such as criteria selected for inclusion of
patients, definitions, medical facilities, time and type of
follow-up, and interrelationships between sociodemographic
factors.
Age at onset. The course and prognosis of childhood
lupus has traditionally been considered less favorable than
that of adults. Renal and skin disease, fever, lymphadeno-
pathy, vasculitis, seizures and serological abnormalities, as
well as high levels of anti-DNA antibodies and low levels of
complement, seem to be more frequent in younger SLE
patients [6,13]. Older patients more commonly have
interstitial lung disease, Sjogren s syndrome, musculoske-
letal manifestations, serositis and myocarditis [13].
Although survival of pediatric lupus patients has been
found to be shorter than that of older patients, especially
when nephritis is present, the prognosis of lupus in
childhood has also improved considerably in the last few
years [14]. Actually, some researchers have found no
relation between age at onset and survival in SLE [7] and
others have even shown that older SLE patients have
decreased survival [15]. Patients with disease onset before
age 20 or after 50 could have a poorer outcome than those
whose disease initiates between age 20 and 50. Younger
patients tend to die more frequently from infection and lupus
activity, whereas older patients die from cardiovascular
complications and neoplasms [15].
Race and socioeconomic status. Most studies that
have investigated differences between black and white SLE
patients in the United States have shown that black patients
have a poorer outcome, indicating a prognostic role of ethnic
factors in SLE [15]. However, black patients also frequently
have lower socioeconomic status, which has also been
associated with poor prognosis in SLE and other chronic
diseases [16]. Indeed, poverty may be an important
determining factor in the prognosis of SLE patients in
Hispanic communities in the United States or developing
countries. This has not been sufficiently studied, but it is
known that low income and scant education are associated
with difficulties in access to health care, in ability to
understand and recognize SLE symptoms, in the capacity to
carry out medical recommendations, and in deficient social
support, nutrition and employment opportunities [16]. Thus,
black and Hispanic SLE patients from Los Angeles who had
attained high socioeconomic status were found to have a
prognosis similar to that of Caucasian whites [6]. A
multicenter study in the U.S. showed that privately insured
SLE patients had better survival at 1, 5 and 10 years (92%,
85% and 71%, respectively) than publicly insured patients,
in whom survival was 86%, 68% and 53%, respectively [17].
One recent study of lupus populations in Alabama and Texas,
with equivalent proportions of Caucasians, African Ameri-
cans and Hispanics, found that genetic, ethnic and socio-
economic factors were associated both with organ disease
presentation and with lupus activity [18]. Hispanic patients
with the lowest socioeconomic status (43% of them being
below poverty line) also had more cardiac and renal
manifestations at the onset of lupus, and reached higher
disease activity [18].
Gender. The influence of gender on survival of patients
with SLE is controversial. Some studies did not show
important differences in spectrum and disease severity or
survival [15,17] between males and females. Others found
that survival in males tends to be lower [6]. A joint study in
107 male SLE patients from Mexico and Colombia found
them to have increased frequency of nephropathy and
vascular thromboses, as well as higher levels of anti-DNA
antibodies and corticosteroid requirement than did 1,209
female SLE patients [19]. SLE-related death, particularly
due to nephritis, was also more frequent in male patients
[19].
· SLE-related factors
Renal involvement. Multiple studies have shown that
nephropathy is one of the most important factors determin-
ing decreased survival in SLE [6,8,10,12,17]. The strongest
clinical indicators of mortality in patients with lupus
nephropathy are increased serum creatinine at onset,
hypertension, and the degree of proteinuria [12,17]. Survival
analyses, according to kidney biopsies, have shown that
proliferative and chronic lesions as well as a high score for
renal disease activity index were associated with poor
prognosis [12, 20].
Central nervous disease. Neuropsychiatric lupus in-
cludes a wide spectrum of neurological symptoms, some
directly related to active lupus, others associated with
antiphospholipid antibodies, and yet others reflecting
infections, hypertension and metabolic complications or
drug-related problems. CNS involvement was considered a
poor prognostic factor in the past [17]. However, other
studies found no influence of these manifestations on the
survival of patients with SLE [21]. When stratified into focal
and diffuse neurological involvement, only the focal factors,
including stroke, seizure, transverse myelitis, myopathy and
neuropathy, adversely influenced the long-term prognosis of
SLE [21].
Antiphospholipid syndrome. Several individual mani-
festations related to antiphospholipid antibodies, such as
thrombocytopenia, arterial occlusions, venous thrombosis
and hemolytic anemia, were found to be linked to decreased
Reviews
IMAJ · Vol 2 · May 2005
The New Prognosis of SLE
383
Page 3
survival in a cohort of 667 Mexican patients with SLE [8].
This was also observed in SLE patients with antiphospho-
lipid syndrome. Other authors also found a relationship
between thrombocytopenia [12,15], thromboembolism [12]
and a poor prognosis in SLE patients.
Disease activity and vasculitis. Patients with high
lupus activity have increased risk for mortality, as shown in
reports that included diverse disease activity indices [12].
The association of vasculitis as a manifestation of disease
activity with increased mortality in Latin American SLE
patients has recently been recognized [12,22], particularly
when of visceral location [22].
Causes of death in SLE
Improved survival has also brought a change in the causes of
death in SLE patients. Earlier studies noted that most
patients died in the first years of the disease due to severe
disease manifestations (e.g., nephritis, diffuse vasculitis and
central nervous system disease). Other patients died from
infections, frequently also associated with active disease.
Infection remains an important cause of death throughout
the course of illness. Recent studies from developed
countries have emphasized a bimodal pattern of death in
SLE, where deaths occurring within 5 years of diagnosis are
more frequently due to active disease [9]. A second
mortality peak occurs at around 13 years after diagnosis
and is due to cardiovascular complications and end-organ
failure not related to active lupus [9]. The prevalence of
cardiovascular phenomena as causes of death in SLE has
increased from 0% in the pre-steroid era to 15 25% in
recent studies [6,9]. A multicenter European study noted
that thromboses associated with antiphospholipid antibodies
was another predominant cause of death in 12 of 45 patients
who died at 5 years of follow-up [10].
Morbidity and disability
Morbidity and disability caused by a chronic disease such as
SLE may result from acute or persistent severe disease
activity, which produces specific organ damage directly
related to the disease or as a consequence of its therapy.
Frequently, morbidity is aggravated by low socioeconomic
status and inadequate psychosocial support [23].
Specific organ damage
Long-term complications resulting either from SLE or as a
consequence of its therapy may cause chronic damage in
several organs or systems. Chronic manifestations directly
related to SLE or to a secondary antiphospholipid syndrome
that may yield a high morbidity include: cognitive impair-
ment, cardiovascular and cerebrovascular disease, pulmo-
nary hypertension, shrinking lung, renal failure, discoid skin
lesions, and Jaccoud-like arthropathy.
· Damage index
Recently a damage index to estimate morbidity in SLE was
developed and validated [24]. The Systemic Lupus Interna-
tional Collaborating Clinics/American College of Rheuma-
tology Damage Index (SLICC/ACR damage index) was
created to estimate irreversible damage, regardless of
cause, in 12 organ systems related to SLE, its treatment
or intercurrent illness [24]. When applied to the Hopkins
Lupus Cohort, it revealed that irreversible damage had
occurred in the musculoskeletal system in 25% of patients,
at the neuropsychiatric level in 15%, in the eyes in 13% and
in the kidneys in 12% [25]. Avascular necrosis of bone,
osteoporotic fractures and cataracts, the most common
forms of damage found in that study, were linked to
corticosteroid therapy rather than to SLE itself [25].
· Cognitive dysfunction
Neurocognitive deficits evaluated by psychometric test-
ing and characterized by impaired attention, memory,
language and psychomotor speed are more frequent in
SLE patients than in controls, appearing even in patients
without overt CNS manifestations and independent of
disease activity. The course is frequently fluctuating, and
is possibly associated over time with persistent anticardio-
lipin antibodies [26]. Studies designed to estimate both the
pre-morbid level of functioning in patients with cognitive
dysfunction and the impact of cognitive dysfunction on
social, educational and occupational functioning are still
needed.
· Cardiovascular and cerebrovascular diseases
Cardiovascular disease has been recognized as a major cause
of morbidity in SLE patients. The cumulative incidence of
angina or myocardial infarction in a young cohort of SLE
patients from Baltimore was as high as 8%, with 53% having
three or more risk factors to develop coronary artery
disease [27]. The best predictors of coronary artery disease
in SLE patients were age, the length of time on prednisone
treatment, hypertension, hypercholesterolemia and obesity.
A recent study found sustained hypercholesterolemia in
40% of patients with SLE tested within 3 years of diagnosis
[28]. It was associated with older age at onset, increased
cumulative dose of steroids, and no antimalarial therapy.
Risk of hospitalization for acute myocardial infarction,
congestive heart failure or cerebrovascular accident is
increased in young women with SLE as compared to young
women without SLE. All this information points to the
importance of preventive measures to reduce modifiable
risk factors for cardiovascular and cerebrovascular diseases
in the management of SLE patients.
· End-stage renal disease
End-stage renal disease may develop in 5 26% of patients
with lupus nephritis [29,30]. Normal initial serum creatinine
levels or resolution of renal functional abnormalities within
one year were observed to correlate with a lower risk of
renal failure in these patients [29]. Hypertension and
smoking are important and potentially modifiable factors
that influence the prognosis of patients with lupus nephritis.
Diffuse proliferative glomerulonephritis, high activity and
chronicity indices, and the presence of tubulo-interstitial
nephritis are biopsy findings that predict end-stage renal
disease [30]. On the other hand, there seems to be a
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384
C. Drenkard and D. Alarcon-Segovia
IMAJ · Vol 2 · May 2005
Page 4
tendency toward decreased clinical and serological activity
after end-stage renal disease ensues. SLE patients are good
candidates for dialysis and renal transplantation, having
similar graft survival to that of non-SLE patients. Disease
activity and recurrence of lupus nephritis are rare after
transplantation [30]. A recent study found a higher risk of
allograft loss in SLE patients than in non-SLE controls [31].
The presence of antiphospholipid syndrome and a history of
having smoked may associate with decreased survival of
transplanted kidneys [31].
· Infections
Infections have a high impact on the survival and morbidity
of SLE patients. It is known that activity of SLE and
impairment of the immune response relate to the increased
risk of infection [32]. Pryor et al. [33] observed a higher
prevalence of infection in patients treated with cyclo-
phosphamide (45%) than in those on high dose corticostero-
ids (12%). The route of administration of cyclophosphamide
(oral vs. intravenous) did not influence the prevalence of
infection. Risk factors for infection vary for different agents,
e.g., common bacterial organism or opportunistic infections.
The latter are more frequent in patients with multi-organ
disease than in those with any single organ manifestation,
and correlate with higher corticosteroid dose, the use of
cytotoxic drugs, and lower white blood cells at the nadir
[33]. The incidence of infections in SLE patients treated
with prednisone increases when doses are higher than 20
mg/day and administered for longer than 4 weeks. Patients
treated with low doses of corticosteroids, however, are not
spared the risk of infections. Thus, immunosuppressors and
corticosteroids should be used as moderately, as infre-
quently, and as briefly as possible.
Disability, health status and quality of life
SLE has a high impact both on the physical state of patients
and on their psychological and social lives. The recent
interest among researchers in measuring the perception that
SLE patients have about their health status and non-medical
aspects of their lives has prompted the use of several
questionnaires. Some of these instruments, whether arthri-
tis-specific or generic, were designed to determine physical,
psychological and social disability, and have recently been
introduced and recommended for use as outcome measures
to be used in clinical trials in SLE [34].
· Health status and quality of lfe
When compared to healthy controls, SLE patients have a
poor perception of their general health, feeling affected in
their physical function, vitality, social functioning, and
mental health. They also have increased complaints of
bodily pain and fatigue [35]. Some of the items included in
health status instruments, in which SLE patients showed
poor performances, were associated with higher disease
activity, higher cumulative organ damage, lower social
support, and less patient satisfaction with health care [35].
In addition, lower self-efficacy in disease management,
lesser social support, and younger age at diagnosis are
associated with higher disease activity. Ward et al. [23]
observed that physical disability was related to depression,
SLE disease activity to less social support, and cumulative
organ damage to lower self-esteem and time orientation
favoring the present over the future.
In a recent study from Israel comparing the quality of life
of SLE patients with that of healthy controls [36], SLE
patients were found to be more dissatisfied with their health,
job, life satisfaction, active recreation, and independence.
There was no association between quality of life scores and
disease activity index, but lower scores of quality of life
were found in patients with SLE and fibromyalgia as
compared to SLE patients without fibromyalgia. These
findings support the notion that specific psychosocial and
physical interventions should be added to conventional drug
therapy in order to obtain an optimal management of
patients. Better control of fibromyalgia may also contribute
to improving the quality of life in SLE.
· Fatigue
Chronic fatigue is a debilitating symptom that limits daily life
activities and has a negative impact on the health status of
SLE patients. Disease activity or fibromyalgia are consid-
ered as the main primary causes of fatigue in SLE. More
recently, sleep disruption and, to a lesser degree, depres-
sion, have been considered the main direct mediators of
fatigue in SLE patients [37]. On the other hand, another
study found that a primary sleep disorder characterized by
abnormalities in respiration and movement was common in
SLE patients and related to restlessness and poor sleep at
night [38]. This resulted in daytime sleepiness and fatigue.
In addition, close to 40% of SLE patients have symptoms of
depression, which can increase their fatigue and disability
associated with other disease manifestations, decrease their
physical activity, and interfere with their adherence to
treatment. These findings suggest that, in addition to drug
therapy, effective strategies for alleviating fatigue may
include interventions for the detection and treatment of
sleep pathologies and depressive symptoms.
Sustained remission
A few studies have described the clinical course of SLE,
most of them stressing alternating periods of disease
activity in one or more systems with periods of remission.
Although long periods of treatment-free remission in
patients with SLE were reported decades ago, somehow
the notion that this could be achieved became lost until our
observation that 156 of 667 Mexican patients underwent
remission at least once during a mean follow-up of 11.6
years [1].
Remission was defined as at least one continuous year
during which lack of clinical disease activity permitted
withdrawal of all treatment for lupus proper. The duration of
quiescent disease without therapy for SLE surely implies a
previous much longer period without symptoms while drugs
were being progressively withdrawn. According to our
definition, we found 2.8 new cases of remission per 100
Reviews
IMAJ · Vol 2 · May 2005
The New Prognosis of SLE
385
Page 5
patients per year of follow-up. Treatment-free remission
averaged almost 6 years in the 156 patients, representing
half the time of total follow-up of the entire group. In some
of the patients remission lasted up to 18 years, and most of
them continue to be in remission almost 10 years later.
Sixty-two of the 156 patients underwent remission within 2
years of the first clinical manifestation attributable to SLE,
advocating the notion, also observed by others, that many
SLE patients have active disease in the initial period
followed by long remission periods. The mean length of
time from SLE onset to the first remission was of 7.5 years
in our 156 patients, with a range of 0.5 31.7 years. Thus,
although the remission that occurred in most patients
preceded the first 8 years of disease, some of them may
need longer. According to a recent study from Spain [39],
SLE patients with higher initial SLEDAI do achieve
remission, although it may take longer to achieve than in
those with lower initial disease activity indices. Gladman
and coworkers [40] described SLE patients with low C3
determinations and/or high DNA uptakes despite having
quiescent disease. However, most of our patients in clinical
remission also had negative serological tests most of the
time [1].
In our patients, 75 of the 156 who underwent remission
had a subsequent relapse. Most of them, however, remitted
again, and by the end of follow-up 73% of patients were still
in remission. Although there were relapses after as many as
14 years of remission which, due to continued close
observation, were promptly treated, the probability of
undergoing remission increased with disease duration,
reaching 70% of patients at 30 years. Remission was
achieved in patients with mild disease as well as in those
with severe initial renal, CNS or hematological disease. This
was also stressed by Formiga et al. [39], who found no
differences in the major initial clinical manifestations nor in
the treatment of patients who achieved remission and those
who did not.
Other studies have observed prolonged remissions in
both adults and children with severe SLE who received
different therapies. Interestingly, in a case-control study
involving our same cohort we found that early occurrence of
inflammatory myopathy was a strong predictor of subse-
quent remission. This could not be attributed to inclusion of
patients with mixed connective tissue disease within our
lupus cohort since we took great care to avoid it.
In our study, 2 of the 156 patients who achieved remission
and 48 of the 511 who did not died during follow-up [1]. The
two survival curves differed significantly. The better
survival of patients who achieved remission occurred
independently of the effect of disease manifestations (such
as nephropathy and thrombocytopenia), which were found to
cause increased mortality in our cohort [8].
Conclusions
Most SLE patients are now living longer and leading better
lives than in the past. Survival is increasing faster in SLE
patients than in the general population. The recognition and
consequent reduction of factors leading to morbidity are
important issues in clinical lupus research, and appropriate
disease control with minimal treatment must always be
sought. Aggressive, toxic and frequently unnecessary treat-
ments in patients with relatively little disease activity may
result in organ damage and should be avoided.
In most SLE patients, lupus disease activity tends to
decrease with time, permitting their management with less
toxic therapy such as antimalarials, or low doses of
corticosteroids. A significant number of patients may
become, at times indefinitely, symptom-free and require no
medication. We hope that physicians will heed the notion
that medication can be stopped in SLE patients; they should
avoid continuing indefinitely, out of groundless fear, with
small doses of prednisone despite complete clinical remis-
sion. Until a cure for lupus is found, achievement of
treatment-free remission must be considered the current
goal in managing lupus patients. Its attainment renders a
positive impact on the overall health status of SLE patients,
not only by reducing the toxic effects of drugs but also by
improving their quality of life in the psychological and social
spheres.
__________________________________________________
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Space does not permit more complete reference listing. It will be provided by the
corresponding author upon request
__________________________________________________
Correspondence: Dr. D. Alarcón-Segovia, Director, Instituto Nacional
de la Nutrición Salvador Zubirán, Vasco de Quiroga 15, 14000 México
D.F., México. email: avilla@aztlan.innsz.mx
Reviews
IMAJ · Vol 2 · May 2005
The New Prognosis of SLE
387