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How to improve morbidity and mortality in systemic - Rheumatology

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Rheumatology 2000;39:238–244
Systemic Lupus Erythematosus/Series Editors: D. Isenberg and
C. Gordon
How to improve morbidity and mortality in
systemic lupus erythematosus
M. B. Urowitz and D. D. Gladman
University of Toronto Lupus Clinic and Centre for Prognosis Studies in the
Rheumatic Diseases, Toronto Western Hospital, Toronto, Ontario, Canada
Evolving spectrum of clinical presentation in
systemic lupus erythematosus (SLE )
T 1. Survival rates in series published from 1955
SLE is a chronic multisystem disorder of presumed
autoimmune origin in which cytotoxic antibodies, or
circulating immune complexes, give rise to tissue damage
often resulting in end organ disease and even mortality.
The first large series to study mortality in this disease
in 1955 revealed a survival of less than 50% at 5 yr [1].
Thus, in the past four decades much of the therapeutic
initiatives in this disease have been directed at controlling the acute organ attack and inflammatory response
in order to minimize tissue damage and to decrease the
very high mortality rates. The therapeutic interventions
have focused on the use of corticosteroids and cytotoxic
agents in appropriate doses to minimize mortality on
the one hand and morbidity from the disease or from
the treatments on the other. This approach has in fact
been quite successful and the overall mortality rates
have improved dramatically over this period of time
[2, 3] ( Table 1). The reported 20-yr survival of 68%
[22] in the 1990s in contrast to the 50% 5-yr survival in
1955 indicates success in controlling the acute immunological injury typical of this condition. Furthermore, we
have shown that this improved survival was greater than
the improvement in survival observed in the general
population during the same time. The standardized
mortality ratios for SLE patients improved from 10.1
in the 1970s, to 4.8 in the early 1980s, and to 3.3 in the
early 1990s [27].
During this period, our prognosis studies and those
of others have demonstrated distinctive mortality and
morbidity patterns in these patients. Patients dying early
usually succumb to active lupus and infection, while
patients dying after 5 yr of disease often die of end
organ dysfunction due to damage from the disease
process or due to degenerative vascular disease manifested arteriosclerotic cardiovascular and cerebral vascular disease. Patients surviving into the later stages of
their disease often manifest morbidity features apparently unrelated to acute immunological inflammatory
Centre
Year
5
10
15
20
Baltimore [1]
Cleveland [4]
New York [5]
New York [6 ]
Toronto [7]
Farmington [5]
Singapore [8]
Los Angeles [9]
Multicentre [10]
Sweden [11]
India [12]
Holland [13]
Alabama [14]
Finland [15]
Los Angeles [16 ]
Stanford [17]
India [18]
CuracВёao [19]
Chile [20]
Durham [21]
Toronto [22]
Malaysia [23]
India [24]
Spain [25]
Denmark [26 ]
1955
1964
1968
1971
1974
1976
1980
1981
1982
1985
1986
1989
1990
1991
1991
1991
1992
1993
1994
1995
1995
1997
1997
1998
1999
50
69
70
77
75
93
70
88
86
97
68
92
89
–
97
88
78
56
92
82
93
82
89
90
91
–
54
63
60
63
84
60
79
76
–
50
87
83
91
93
64
–
–
77
71
85
70
77
85
76
–
–
–
50
53
–
–
74
–
–
–
–
79
81
83
–
–
–
66
63
79
–
60
80
64
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
68
–
–
–
53
% survival at 5–20 yr
Submitted 20 September 1999; accepted 7 October 1999.
Correspondence to: D. D. Gladman.
238
В© 2000 British Society for Rheumatology
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mechanisms. These include: (1) accelerated atherosclerosis (angina, myocardial infarction, peripheral vascular
disease and cerebral vascular disease); (2) dementia
usually presenting as cognitive dysfunction; (3) bone
disease presenting as osteoporosis or avascular necrosis
(AVN ); (4) fibromyalgia and chronic fatigue. Thus, the
challenge for the treating physician is to distinguish
these clinical presentations from features related to
active SLE. For example, chest pain due to either
ischaemic coronary artery disease, pericarditis or fibromyalgia musculoskeletal pain. Thus, an important
contribution to the understanding of the clinical presentation of SLE in the past decade has been the
description of the late-stage mortality and morbidity
features in this condition.
Morbidity and mortality in SLE
Accelerated atherosclerosis
Subclinical atherosclerosis in SLE
Since such a significant number of patients suffered
clinical atherosclerotic events, we turned our attention
to detecting subclinical atherosclerotic disease that
would afford us a better opportunity for intervention
and hopefully prevention of these outcomes. To do this
we employed a dual isotope myocardial perfusion
imaging (DIMPI ) technique using the two isotopes
thallium-201 (201TI ) and technetium 99m-sestamibi
(99mTc sestamibi) following a dipyridamole stress. One
hundred and thirty patients have been studied and 52
or 40% had perfusion abnormalities. Reversible defects
consistent with ischaemia were seen in 47 (90.4%) and
14 (27%) had a fixed defect consistent with previous
myocardial damage. When patients with a previous
history of coronary artery disease were excluded, abnormalities were still found in 33% of these patients with
lupus [28].
Another method employed to detect subclinical atherosclerosis in the general population has been the
ultrasound assessment of the presence of focal plaque
in the common carotid artery. Manzi et al. [31]
employed B-mode ultrasound to study the prevalence
of carotid artery plaque formation in women with SLE
and found that 40% of all lupus patients studied had
focal plaque detected. It is thus remarkable that large
studies of non-invasive assessments such as DIMPI and
carotid ultrasound have all indicated a prevalence of
subclinical disease of approximately 35–40%. These
studies suggest that atherosclerotic disease is prevalent
and present in subclinical form for some years prior to
manifesting as a clinical outcome.
Role of hypercholesterolaemia in accelerated
atherosclerosis in SLE
Since some of the classic atherosclerotic risk factors,
especially cholesterol levels, have been suggested as
predictors for the development of atherosclerosis in
SLE, we studied an inception cohort of 134 patients
seen between 1974 and 1987 with respect to cholesterol
levels. The cohort was divided into three groups: a
group who had normal cholesterol in each of the next
3 yr of their follow-up; a group that had high cholesterol
in each year of the next 3 yr; and a group who had
variable cholesterol elevations in at least 1 or 2 of the
3 yr. The outcome evaluated was the time to a first
coronary event. The results indicated that patients who
had persistently elevated cholesterol had significantly
more coronary events than patients who had normal
cholesterol at all times. Patients with variable cholesterol
levels had an intermediate number of events. Thus,
persistently elevated cholesterol is a significant prognostic factor for an adverse atherosclerotic outcome
[32].
Role of lupus therapy in hyperlipidaemia in SLE
In addition to dietary factors and genetic predisposition
to hyperlipidaemia, therapy has also been found to have
an effect on lipid levels, especially in SLE [33]. Steroid
therapy has been associated with increased total cholesterol, and lipid subfractions including very low-density
lipoprotein ( VLDL-C ) and LDL-C [34]. High density
lipoprotein (HDL-C ) is generally low in active untreated
lupus and may actually increase towards normal in
steroid-treated patients. Higher doses of steroids will
produce an adverse lipid profile and may thus act as a
predisposing factor for atherosclerosis.
With regards to anti-malarial drugs, there is a growing
body of evidence that these agents, in addition to their
effects on disease activity, may also have beneficial
effects on lipid profiles of patients with lupus. We have
demonstrated that initiating anti-malarials in patients
not receiving corticosteroids lowered total cholesterol
levels but only temporarily [35]. However, in patients
receiving a stable dose of steroids there was a statistically
significant reduction in total cholesterol over 6 months
and in patients using anti-malarials prior to initiation
of corticosteroids there was also a lowering of the
incidence of steroid-induced hypercholesterolaemia [35].
Anti-malarials were successful in lowering total cholesterol, LDL, and VLDL [36 ]. The effect was perhaps
greatest on VLDL both in the fasting and in the nonfasting state. Thus, we have shown that hypercholesterolaemia was a poor prognostic factor for atherosclerotic
outcomes, and that anti-malarials could minimize the
steroid-induced hypercholesterolaemia.
Other cardiac risk factors in SLE
In addition to lipid abnormalities, there is evidence that
other risk factors for coronary artery disease described
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Clinical atherosclerosis in SLE
Recent studies in our cohort revealed that at any point
in time 13% of patients will have features of clinical
atherosclerosis either manifested as angina, myocardial
infarction or peripheral vascular disease alone or in
combination. A similar prevalence of myocardial infarction and angina has been noted in other established
lupus cohorts, including the Pittsburgh and the
Baltimore cohorts [28–30]. Furthermore, of 124 patients
who died between 1970 and 1993 in our clinic, 40 had
had post-mortem examinations [22]. Of these, 21 or
52.5% had evidence of moderate to severe atherosclerosis
at the time of death either as a coexistent finding or as
a primary cause of death. Furthermore, epidemiological
studies have also confirmed this increase in coronary
artery disease. In 1993–1994 the annual incidence of
myocardial infarction in Canadian women was estimated
at 0.001. This compares with incidence rates for women
in our lupus cohort of 0.005. Thus, in women with lupus
there was a five-fold increase in the incidence of
myocardial infarction. Moreover, the median age of
myocardial infarction in Canadian women was 65–74 yr
compared with 49 yr in the lupus cohort. Similar epidemiological findings have been noted in the Pittsburgh
cohort where women age 35–44 yr were found to be
52.4 times more likely to have a myocardial infarction
than controls [29].
239
240
M. B. Urowitz and D. D. Gladman
in the general population may be of some importance
in SLE. Hypertension was found to be important in the
Pittsburgh study of carotid artery plaque in these
patients [31]. Hypertension may be associated with
active lupus, renal disease and steroid therapy itself, and
it is therefore not surprising that it is a common risk
factor seen in patients with SLE [37]. Other risk factors,
such as sedentary lifestyle, are common in SLE because
of the fatigue associated with the disease and the possible
bone and joint injury from the disease or its treatment.
known about the investigation and treatment of this
condition to effect a significant impact on morbidity
and mortality from atherosclerosis in these patients in
the later stages in their disease. Rheumatologists need
only develop the resolve to assume the primary role in
screening and co-ordinating the management of coronary artery disease and its risk factors in these high-risk
patients.
Lupus as a risk factor for accelerated atherosclerosis
Finally, when patients with SLE were compared with a
cohort of patients with accelerated atherosclerosis without connective tissue diseases with respect to classic risk
factors for atherosclerosis, it was found that patients
with lupus generally had one risk factor less than
patients with accelerated atherosclerosis and no history
of lupus [38]. This may suggest that SLE on its own
should be listed as a risk factor for accelerated atherosclerosis similar to diabetes.
Patients with SLE complain of memory loss and loss of
concentration, even in the absence of obvious neuropsychiatric manifestations. Neuropsychological testing has
been increasingly used in the assessment of patients both
to confirm the presence of active central nervous system
(CNS ) disease as well as to detect abnormalities in those
without overt active cerebral disease [40–47]. This dysfunction is likely multifactorial. Early in the disease it
may reflect active neuropsychiatric lupus and late in the
course neurodegenerative disease secondary to previous
immune damage or therapy for SLE. It has also been
suggested that some of the abnormalities detected among
patients with SLE may be due to depression or other
psychiatric illness in these patients. Also, chronic prednisone therapy has been reported to impair memory
[48]. We compared 58 patients with totally inactive SLE
(SLEDAI = 0) and 47 healthy controls using a battery
of standardized neuropsychological tests to evaluate
neurocognitive function. This study showed that 43% of
patients with inactive SLE had evidence of neurocognitive dysfunction compared with only 19% of controls.
The neurocognitive dysfunction was not explained by
psychiatric illness, abnormal neurophysiological studies
(brain scan, electroencephalogram) or previous major
organ involvement of SLE, atherosclerotic complications, or steroid therapy [49]. Two recent studies suggest
that anti-cardiolipin antibodies may play a role in the
neurocognitive dysfunction documented in patients with
SLE. Although these studies used different methods to
define abnormalities in neurocognitive function, they
both suggest an association between anti-cardiolipin
antibodies and neurocognitive dysfunction. Hanly et al.
[50] studied 51 patients with SLE of whom 57% had
persistently elevated anti-cardiolipin antibodies over a
5-yr period. They showed that persistent IgG anticardiolipin antibodies were associated with a reduction
in psychomotor speed, whereas IgA anti-cardiolipin
antibodies were associated with impaired conceptual
reasoning and executive ability. Menon et al. [51]
demonstrated that persistently elevated levels of IgG
anti-cardiolipin antibodies over a 2–3-yr period were
associated with poorer performance in cognitive
function, particularly in tasks requiring speed of attention and concentration. It is not yet clear whether
patients with SLE neurocognitive dysfunction and anticardiolipin antibodies require anti-coagulation or
whether treating patients with anti-cardiolipin antibody
with anti-coagulants could prevent this outcome. These
questions can only be answered with prospective studies.
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Management of atherosclerosis risk factors in SLE
It is now clearly shown that accelerated atherosclerosis
is a common presentation in late-stage SLE, and therefore patients should be regularly screened to assess the
prevalence of coronary artery disease risk factors. We
have shown that certain traditional factors, such as
cholesterol, play an important role in the development
of this disease and these potentially reversible factors
should be targeted for intervention. Since patients with
lupus are already starting with one risk factor, that is
their disease, other risk factors should be interpreted
and managed with that in mind. For patients shown to
have sustained hypercholesterolaemia, an active management strategy should be undertaken to minimize the
dose of steroid where possible, and consider steroidsparing agents, especially anti-malarials, which have a
lipid-lowering effect. Dietary advice and lipid-lowering
drugs should be instituted early where indicated. Other
factors, such as blood pressure, smoking and sedentary
lifestyle, should be addressed. These facts are clear and
it is also clear that rheumatologists and internists have
the expertise to follow through on each risk factor
investigation and treatment. Unfortunately they do not
always do this. In a recent quality improvement study
of the Toronto cohort, we found that there was variability in physicians’ management of risk factors for coronary artery disease [39]. In general rheumatologists
performed well in minimizing steroid use, controlling
disease activity and managing hypertension. However,
there was much inconsistency in the approach to other
metabolic and lifestyle factors such as hyperlipidaemia,
obesity, and smoking.
While rheumatologists continue to anticipate the time
when effective anti-immunological medications will treat
the acute disease process in SLE, they can contribute
significantly to decreasing mortality in SLE by focusing
on the early diagnosis and preventative therapy of
atherosclerotic disease in late-stage lupus. Enough is
Cognitive dysfunction in SLE
Morbidity and mortality in SLE
Although the pathogenesis of neurocognitive dysfunction in patients with SLE remains unclear, it is important
that when patients complain of neurocognitive impairment they be tested formally. This provides an opportunity to confirm their dysfunction and follow it. If there
is evidence of active neuropsychiatric lupus, or depression, these illnesses should be treated. Patients with
evidence of previous CNS clots associated with anticardiolipin antibodies will already be receiving
anti-coagulation. Further study to elucidate the mechanism(s) of this early dementia are needed to develop
prevention strategies for this problem. In the interim,
approaches to help patients cope with this disability
must be developed.
Bone disease in SLE
AVN in SLE
AVN is a common complication among patients treated
with corticosteroids. It has been reported in 10–30% of
unselected patients with SLE [58]. The hip is the most
commonly involved joint, but most joints in the body
can be affected. Up to two-thirds of patients with AVN
will have multiple sites and typically will have been on
high-dose corticosteroids at some time during the course
of their illness. There is no clear association with any
specific manifestation of SLE, or anti-cardiolipin antibody [59]. The nature of the early lesion of AVN in
SLE is unknown, but may be elucidated with current
imaging techniques such as magnetic resonance imaging
(MRI ) [60]. AVN frequently results in surgical intervention, often total joint replacement. Since this complication is so prevalent and leads to significant disability in
young females, measures to lessen its occurrence are
important. Steroid use should be minimized using
steroid-sparing agents as appropriate.
Fatigue in SLE
Fatigue is a very common symptom in SLE and occurs
at any time in the course of the disease, even in its
inactive phase [61]. Fatigue correlates with fibromyalgia
[62], sleep abnormalities [63], depression [64] and poor
quality of life [61–63], and is thus a major determinant
of morbidity in SLE. Studies are currently underway to
elucidate the mechanisms of fatigue in SLE. Until these
mechanisms are fully understood, physicians should
treat fibromyalgia [65, 66 ], depression and altered sleep
physiology with standard approaches.
In addition to the spectrum of features of longstanding SLE, several other factors contribute to the
morbidity among patients with this disease. These
include persistent or reactivation of inflammatory disease, infections, and other damage which results from
both the disease process and its therapy.
Persistent inflammation and reactivation of lupus can
occur late in the course of SLE [11]. It is generally
believed that disease activity improves in SLE patients
who develop end-stage renal disease [67]. However,
recent studies using validated measures of disease activity indicate that there is no decrease in the flare rate
during dialysis or transplantation [68, 69]. While it has
been suggested that patients with lupus usually flare in
the same systems they presented with originally, there
is evidence that new organ system involvement can
occur at subsequent exacerbations of the disease [70].
At the University of Toronto Lupus Clinic we observed
the onset of new disease manifestations after 5 yr of
entry to the clinic in 12% of the patients. Thus, patients
with SLE should be followed carefully, even when they
have demonstrated clinical and laboratory remission.
Infection poses a risk for both mortality and morbidity in patients with SLE throughout the course of their
disease [71, 72]. There can be multiple system involvement, usually with common organisms, often bacteria,
but some opportunistic organisms. Both active disease
and drug therapy have been incriminated as risk factors
for infection. Indeed, in a recent study of SLE patients
from our centre, the two major factors associated with
infection in a multivariate analysis were the use of
steroids and immunosuppressives.
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Osteoporosis in SLE
Corticosteroids are a known risk factor for the development of osteoporosis. As long as steroids remain the
cornerstone of therapy for SLE this complication will
have to be addressed. In addition, as patients with SLE
survive longer and reach menopause, the postmenopausal state will be an added risk factor for this
complication. Furthermore, patients with SLE are at
risk of premature menopause both as a result of the
disease or its therapy. Osteoporosis has been formally
assessed in pre-menopausal women with SLE using bone
density studies [52–54]. These studies revealed that bone
mineral density was lower in SLE patients compared
with controls. In addition, these studies suggest a multifactorial aetiology for the osteoporosis as corticosteroids
did not appear to be the only determining factor. Similar
findings were documented in post-menopausal females
with SLE [55]. Furthermore, this osteoporosis is often
clinically symptomatic, as in a study of 702 women with
SLE 12.3% reported at least one fracture following the
diagnosis of SLE [56 ]. Women with lupus were almost
five times more likely to have a fracture than women of
similar age from the US population sample. These
studies all indicate that patients with SLE should be
treated prophylactically for this complication, and have
routine monitoring with bone density studies. Premenopausal women with SLE given corticosteroids
should be routinely treated with calcium and vitamin D.
In those who develop frank osteopenia bisphosphonates
should be prescribed to prevent complications such as
vertebral collapse or peripheral fractures. Postmenopausal women with SLE should in addition to the
above treatment be offered hormone replacement. Our
studies have indicated that flares in women given hormone replacement therapy are no more frequent than
in SLE patients not taking these medications [57]. This
pre-emptive approach to the diagnosis and treatment of
osteoporosis could lead to a significant decrease in
morbidity in these patients.
241
242
M. B. Urowitz and D. D. Gladman
Summary
As patients with SLE live longer, their disease manifestations vary significantly with each epoch of the disease.
Many of the causes of morbidity in patients with SLE
are related to therapy. Thus, physicians should always
be conservative in the doses of steroids used, and use
steroid-sparing agents judiciously. Until newer therapeutic modalities become available to treat the immunological disease more effectively, the greatest impact on
mortality and morbidity may be achieved by controlling
the late-stage manifestations.
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M. B. Urowitz and D. D. Gladman
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