Rheumatology 2002;41:1095–1100

Review

Long-term complications of systemic lupus

erythematosus
C. Gordon
University of Birmingham, Birmingham B15 2TT, UK

Systemic lupus erythematosus (SLE) is still a disease whether they are due to effects of the disease itself,
with significant mortality. Although 5 yr after diagnosis the therapies used, or co-morbid disease (perhaps with
92% of patients are alive, the prognosis falls to 82% associated underlying disease mechanisms or linked
survival at 10 yr, 76% at 15 yr and only 68% at 20 yr genetic predisposition).

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in Toronto w1x. There has been improvement in sur-
vival, with the standardized mortality ratio in patients
recruited to the Toronto cohort in 1970–1977 being 10.1 Chronic damage
(95% CI 6.5–15.0), compared with 3.3 (95% CI 1.8–5.7)
Chronic damage in lupus patients is defined as non-
for those recruited between 1986 and 1994 w2x. Data
reversible change, present clinically, that has developed
from other centres in the USA and Europe has been
since the onset of lupus. The assessment of damage has
similar. Studies published around 1980 found that about been facilitated by the development of the Systemic
80% of patients survived 5 yr and about 60% of patients
Lupus International Co-operating Clinics and American
survived 10 yr. More recent studies have shown that
College of Rheumatology (SLICCuACR) damage index
5-yr survival is now nearer 90–95% and that 70–85% (DI) w7, 8x. This SLICCuACR DI covers 39 items that are
of patients survive 10 yr w3x. In most studies, patients
divided between 12 systems. It has been shown to have
with renal involvement have had a poorer prognosis
construct validity and reliability, and is distinct from
than those without renal disease. Nevertheless, survival
disease activity. However, the DI score increases more
has shown improvement in those with renal disease
in patients with active disease at two time points 5 yr
presenting to a UK centre between 1976 and 1986 (81%
apart, than it does in those with less active disease w7, 8x.
10-yr survival), compared with those presenting between
Renal or pulmonary damage within 1 yr of diagnosis
1963 and 1975 (56% 10-yr survival) w4x.
has been shown to predict patients at risk of dialysis
The commonest cause of death has been infection,
or death within 10 yr of diagnosis w9x. The increased risk
both in early and late deaths w1, 3x. Active SLE
of death in those with early damage (within 2 yr of
contributes to about a third of early deaths but less diagnosis) was also demonstrated in further studies from
commonly to late deaths. However, deaths related to
the SLICC group and the Toronto group w10, 11x.
acute and chronic vascular disease including sudden
About 40% of the Birmingham lupus cohort patients
death are more common in those dying more than 5 yr
have developed at least one item of damage. The most
after diagnosis. However, there is more to prognosis
often involved systems are musculoskeletal (15%
than just death. There is considerable morbidity asso-
patients), neuropsychiatric (11% patients) and cardio-
ciated with more prolonged survival after the diagnosis
vascular (9% patients). The least commonly affected
of SLE. Most physicians caring for lupus patients will
systems are malignancy (3% patients), diabetes mel-
be familiar with patients in whom active disease has
litus (3% patients) and premature gonadal failure (2%
resolved but the patients have suffered from symp-
patients) (unpublished observations). The remainder
toms related to the accumulation of chronic damage w5x. of this review will address just three of these long-term
Both active disease and damage can be associated with
complications of lupus: vascular disease (the major
impaired quality of life and reduced functional ability,
cause of neuropsychiatric and cardiovascular damage),
although other factors such as the psycho-social back- osteoporosis (potentially the most avoidable item of
ground of the patient will affect a patient’s perception of
musculoskeletal damage) and malignancy (an item of
their disease as well w6x. Having improved therapy for
damage of debatable association with lupus disease and
active lupus disease, the challenge is now to understand
its treatment).
and prevent the long-term complications of this disease,

Submitted 28 November 2001; revised version accepted 5 April
2002.
Correspondence to: C. Gordon, Department of Rheumatology,
Division of Immunity and Infection, The Medical School, University
of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
Coronary artery disease in SLE patients
The commonest form of cardiovascular damage is
coronary artery disease. Urowitz et al. w12x first drew
attention to this when he reported a bimodal pattern of

1095 ß 2002 British Society for Rheumatology

1096 C. Gordon
mortality in SLE, with early deaths due to lupus and late
deaths due to myocardial infarction in the Toronto
cohort. Subsequently, Petri et al. w13x reported that 30%
of the deaths in the Hopkins lupus cohort were due to
coronary artery disease. In 1997, Manzi et al. w14x
showed that the relative risk for a myocardial infarction
in women with lupus aged 35–44 yr was 52.3 times the
risk for women without lupus. Most surprisingly, two
thirds of all coronary events in this cohort were in
women under the age of 55 yr w14x. Recently, Bruce et al.
w15x confirmed a low age of onset of coronary artery
disease in the Toronto cohort. They found that the mean
age for myocardial infarction in the lupus patients was
49 yr whereas the peak incidence in the local general
population was in the group aged 65–74 yr w15x.
However, there is some variation between cohorts. In
a recent review, Petri w16x discussed 13 studies showing
that the prevalence of coronary artery disease in lupus
patients varied from 6 to 54% and the mortality from
this condition varied 3–45%. This is likely to reflect the
different patient populations reported in these studies.
In California, the risk of hospitalization of lupus pati-
ents aged 18–44 yr due to acute myocardial infarction,
congestive cardiac failure and stroke is over seven times
that of women without lupus in California w17, 18x.
Unfortunately, this risk of premature vascular disease is
still not widely appreciated. I am aware of casualty staff
in the UK who have sent home women with lupus and
chest pain without full assessment, on the grounds that
they are too young to have ischaemic heart disease,
when they were actually suffering from acute myocardial
infarction in their late 30s. This problem is not restricted
to lupus patients in the UK however, as women with
ischaemic heart disease without lupus have been turned
away from emergency rooms in the USA as well w19x.
The above studies have shown that risk factors
for coronary artery disease in SLE include older age
at diagnosis, longer disease duration, longer steroid use
(especially higher cumulative dose), hypercholesterol-
aemia, hypertension, post-menopausal status, obesity,
diabetes mellitus. In some studies additional risk factors
include pericarditis, myocarditis, raised homocysteine
levels, anti-phospholipid antibodies (lupus anticoagu-
lant), male sex and renal insufficiency. However, there is
still something about lupus disease itself which seems to
confer the greatest risk for coronary artery disease and
the underlying cause for this remains uncertain. It is
quite possible that the additional risk conferred by lupus
is related to specific effects of this inflammatory and
immune complex mediated disease on blood vessels. But
it is hard to disentangle effects of severe disease from the
effects of high dose steroids as the same patients are
affected by both.
We have demonstrated significantly increased levels of
total cholesterol and triglycerides, and increased small,
more atherogenic, LDL subfractions in SLE patients
compared with controls. There is also a higher level of
lipid hydroperoxides consistent with oxidative stress
in the SLE patients w20x. Bruce et al. w15x have shown
that SLE patients with sustained increase in cholesterol
are most likely to develop coronary artery disease.
Sustained hypercholesterolaemia is associated with
cumulative steroid dose, absence of anti-malarial therapy
and onset of lupus at greater than 35 yr old in the
Toronto cohort w21x. In an attempt to identify sub-
clinical disease, Manzi et al. w22x has studied the
prevalence of carotid plaque in SLE patients. Out of
175 women of whom 15% had had a previous arterial
event, 40% were found to have focal plaque on B mode
ultrasound. Even in those under 35 yr, 19% had carotid
plaque. Logistic regression analysis showed that the
presence of plaque was independently associated with a
previous coronary event, prolonged steroid use, older
age, higher systolic blood pressure readings and higher
LDL levels. A previous coronary event, older age and
high systolic blood pressure were associated with more
severe plaque formation. Other methods of identifying
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sub-clinical disease include myocardial SPECT scans,
thallium myocardial scans and endothelial function by
brachial artery ultrasound. Studies using these modal-
ities have suggested that 20–40% of SLE patients have
sub-clinical ischaemic heart disease. Methods more
related to clinical disease such as exercise-induced
ischaemia and segmental wall movement by echocardio-
graphy showed only 4–12% of patients were abnormal
w15, 16, 23, 24x.
At the present time the focus of therapy should be to
get optimal lupus disease control with the minimum
of steroids, through the judicious use of anti-malarial
agents and other immunosuppressive agents. Advice
about not smoking, appropriate exercise, low choles-
terol diets, lipid lowering therapy, control of blood
pressure and screening for diabetes mellitus should be
reviewed regularly. The role of folate, B group vitamins
and anti-oxidants such as vitamins E and C remain
uncertain but worthy of further study.
Osteoporosis in SLE patients
Osteoporotic fractures are probably the most pre-
ventable form of musculoskeletal damage. The most
comprehensive study was published by Ramsey-
Goldman et al. w25x in 1999. They found that 86 (12%)
of 702 women with lupus had suffered at least one
self-reported fracture since the onset of SLE. The stan-
dardized morbidity ratio was 4.7 (3.8–5.8). Associations
with time from lupus diagnosis to fracture are very
reminiscent of the risk factors for cardiovascular
disease: older age at diagnosis, longer disease duration,
longer duration of steroid use, post-menopausal status
and, in this case, less use of oral contraceptives w26x.
Furthermore, Ramsey-Goldman and Manzi w27x have
recently shown an association between decreased bone
mineral density (BMD) and both an increased carotid
plaque index and the presence of coronary artery
calcification in a pilot study of 65 women with lupus.
This supports the concept that inflammatory and
immune-mediated mechanisms involved in lupus may
also contribute to the development of atheroma and
osteoporosis.
 Late complications of SLE
Kipen et al. w28x studied 97 female lupus patients with
a mean age of 44.2 yr and found that there was low bone
mass (>1 S.D. below young adult mean) in the spine and
femoral neck in over 40% of the patients. There was
osteoporotic level BMD (>2.5 S.D. below the young
adult mean) in the spine of 13% of the patients and in
the femoral neck of 6% of the patients w28x. There was a
much clearer inverse relation between steroid use ever
and the spine BMD result than the femoral neck BMD.
Even pre-menopausal lupus women have been found
to have reduced BMD. Sinigaglia et al. w29x studied 84
pre-menopausal women (mean age 30.5 yr) and found
that 22% were in the osteoporotic range in at least one
site. Again there was a strong association with longer
disease duration and higher steroid use, as well as
an association with higher SLICCuACR DI score and
low body mass index. Jardinet et al. w30x also found
reduced BMD in the spine of pre-menopausal women
given daily doses of prednisolone of 7.5 mg or more in
a longitudinal study.
In Birmingham we have studied 242 patients, median
age 39.9 yr (range 18–80 yr) w31x. We found that 10%
of our patients were osteoporotic and 41% were osteo-
penic by BMD scanning. Fractures had occurred in
9% of patients since the onset of lupus in the absence
of significant trauma; one in five of those who were
osteoporotic, one in seven of those who were osteopenic
and one in 22 of those with normal BMD at spine and
femoral neck. As with Ramsey-Goldman et al.’s study
w25x, we found that age was the strongest independent
predictor of fracture w31x. Ethnic group, steroid use
and disordered menstrual history were associated with
reduced BMD but not with fractures. Impaired mobility
was strongly associated with low BMD and fractures on
univariate analysis. Multiple logistic regression showed
that age was the best predictor of fractures with a
modified DI score (which excluded fractures as a
damage item) and osteoporotic BMD exerting less
influence. Impaired mobility and menopausal status
were not independent predictors of fractures in our
cohort w31x.
Genetic and environmental factors contribute to the
determination of bone mass and the risk of fracture. The
most relevant risk factors include oestrogen metabolismu
status, sun exposure, vitamin D polymorphismsulevels,
disease activity, levels of bone resorbing cytokines,
development of renal failure, steroid exposure, physical
activity and smoking history. To reduce the risk of
fracture, keep steroid doses as low as possible while
controlling disease activity with the use of other immuno-
suppressive agents if necessary, encourage a good diet
with appropriate physical activity and strongly advise
against smoking, as for the prevention of cardiovascular
disease. Pre-menopausal women should usually be given
high doses of vitamin D3 and calcium, as bisphospho-
nates are contraindicated in those planning pregnancy.
They are retained in the body for long periods even
after therapy has ceased and, in animal studies, have
caused fetal abnormalities w32x. Thus, bisphosphonates
should only be used in pre-menopausal women if they
1097
are likely to require high-dose steroids for a prolonged
period despite the use of steroid sparing agents. They
should have completed their families or be con-
sidered too unwell to be likely to become pregnant in
the future (at least for several years) and they should
be regularly counselled against becoming pregnant on
bisphosphonates.
In post-menopausal women without renal impair-
ment, bisphosphonates are often used as not all women
can tolerate or wish to try HRT. For many years it
has been said that lupus improves after the meno-
pause and that HRT may exacerbate the disease or
prevent this improvement. Studies have shown that
HRT can be used in post-menopausal women with
lupus without increasing disease activity significantly
w33x. Nevertheless, many physicians (including myself)
remain cautious about HRT in patients who have
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had severe disease in the past, particularly if they
deteriorated on oestrogen-containing contraceptive pills
or in pregnancy, or have anti-phospholipid antibodies
w34x. Oestrogen receptor modulators (for example
raloxifene) may be a useful alternative for patients
without pro-thrombotic tendencies. At present, unless
patients with anti-phospholipid antibodies are on war-
farin they should not be given HRT or oestrogen
receptor modulators due to the risk of thrombosis.
Calcitonin provides a useful therapy for patients with
recent fractures as it has some pain-killing properties.
Unfortunately, the intranasal preparation, which is the
most convenient for patients, may be hard to obtain
compared with the subcutaneous form.
Malignancy in SLE patients
The final topic for discussion, the risk of malignancy in
SLE patients, is a less common problem than the issues
discussed above. But it is of considerable concern to
lupus patients and is a subject often raised by them or by
other physicians. If lupus patients develop a cancer or
lymphoma, oncologists often blame immunosuppressive
therapy, even if the patient has only been exposed to the
therapy for a few months. However, there is no data to
support the concept that steroids or cytotoxic agents are
predisposing factors for malignancy in SLE patients,
although there is in rheumatoid arthritis w35x. In lupus
it is possible that disturbances in immune surveillance
are associated with the risk of developing malignancy,
as it is a disease characterized by immune system dys-
function. Certainly, in Sjögren’s syndrome, which is
rarely treated with cytotoxic therapy, non-Hodgkin’s
lymphoma is a well recognized complication w36x.
There have been a number of studies attempting to
establish whether or not there is an increased risk of
malignancy in SLE w37x. Eight cohort studies in which
the standardized incidence rate (SIR) or standardized
mortality rate (SMR) could be calculated are shown in
Table 1 w37–44x. The SIR for malignancy in lupus
patients is greater than 1.0 in all of these studies, but
in only three studies are the SIRs 02.0 with 95%
1098 C. Gordon

TABLE 1. Standardized incidence rates for malignancies in SLE patients

Report No. of No. (%) of

Author type patients malignancies SIR (95% CI)

Pettersson et al. (1992) w38x Cohort 205 15 (7.3) 2.6 (1.5, 4.4)
Sweeney et al. (1995) w39x Cohort 412 20 (4.8) 1.4 (0.9, 2.2)
Abu-Shakra et al. (1996) w40x Cohort 724 24 (3.2) 1.1 (1.1, 1.6)
Mellemkjaer et al. (1997) w41x Cohort 1585 102 (6.4) 1.3 (1.1, 1.6)
Ramsey-Goldman et al. (1998) w42x Cohort 616 30 (4.9) 2.0 (1.4, 2.9)
Sultan et al. (2000) w43x Cohort 276 16 (5.8) 1.16 (0.55, 2.13)
Stahl-Hallengren et al. (2000) w44x Cohort 116 16 (13.8) SMR 1.52M,
SMR 1.12F
Nashi (2000) Cohort 312 22 (7.0) 2.4 (1.5, 3.7)

SIR, standardized incidence rate; SMR, standardized mortality rate.

confidence intervals >1.0 suggesting an increased risk of

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malignancy in SLE patients compared with controls.
Interestingly, these three studies used cancer registry
data, not just a review of medical notes and ques-
tionnaires. Overall, six studies have shown an increase
in non-Hodgkin’s lymphoma, three have shown an
increase in lung carcinoma, one showed an increase in
breast cancer in Caucasian women only, one each have
shown an increase in ovarian, other female genital tract,
and hepatocellular cancer. Five studies have looked
for a relationship to cytotoxic therapy and not found
any association. Not addressed in these studies, but
demonstrated separately, has been an increase in cervi-
cal dysplasia, usually associated with viral infection
and not necessarily related to previous cytotoxic therapy
w45, 46x. It is important that women with lupus receive
regular cervical screening to ensure that they do not
develop cervical cancer.
In Isenberg’s cohort in London w43x, there was no
increase in malignancy compared with the local popula-
tion overall, but there was an increase in Hodgkin’s
lymphoma. Six patients out of 276 followed between
1978 and 1999 had died from malignancy (2.2% of the
cohort). However, malignancy accounted for 23% of
all deaths in this cohort. Our experience in Birmingham
is very similar (unpublished observations). We have
followed an inception cohort of 333 patients since 1991
for a median of 4 yr with a range up to 10 yr. There
have been 25 deaths within the study period. Active
lupus was the primary cause in 8% and a contributing
cause in 13% of deaths. Most patients died of respira-
tory (25%) and cardiovascular (21%) causes. Malignancy
was the third most common cause of death and occurred
in 17% of lupus patients. Thirteen malignancies were
identified in the cohort, giving an overall standardized
incidence ratio of 3.6, and that of non-Hodgkin’s
lymphoma was 29.0. However, in the Toronto cohort,
malignancy accounted for only 7% of early deaths and
6% of late deaths w1, 40x. The SLICC group is currently
organizing a multi-centre, international collaborative
study to assess the risk of malignancy in lupus patients
more reliably, and with enough patients to look at
individual tumours separately and to address the issue
of the role of therapy w37, 47x.
Conclusions
The morbidity and mortality associated with SLE is
still considerable despite improvements in initial immuno-
suppressive therapy for active disease. There is still
much to learn about the long-term complications of
this disease and how best to manage lupus, without
putting patients at risk of additional disease such as
atherosclerosis, osteoporosis and possibly malignancy.
Patients require life-long follow-up by physicians aware
of the broad range of conditions that may ensue. The
lupus patients themselves need to understand why this
is important and their own role in modifying lifestyle
factors that increase the risks of cardiovascular disease
and osteoporosis in particular.
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