REVIEW
Systemic Lupus Erythematosus: Emerging Concepts
Part 1: Renal, Neuropsychiatries, Cardiovascular, Pulmonary, and
Hematologic Disease
Dimitrios T. Boumpas, MD; Howard A. Austin III, MD; Barri J. Fessler, MD; James E. Balow, MD;
John H. Klippel, MD; and Michael D. Lockshin, MD
• Purpose: To review advances and controversies in
the diagnosis and management of systemic lupus ery-
thematosus with visceral involvement (renal, neuropsy-
chiatric, cardiopulmonary, and hematologic disease).
• Data Sources and Study Selection: Review of the
English-language medical literature with emphasis on
articles published in the last 5 years. More than 400
articles were reviewed.
• Dafa Synthesis: Recent debates pertaining to lupus
nephritis have focused on the value of kidney biopsy
data and the role of cytotoxic drug therapies. Many
studies have shown that estimates of prognosis are
enhanced by consideration of clinical, demographic,
and histologic features. For patients with severe lupus
nephritis, an extended course of pulse cyclophospha-
mide therapy is more effective than a 6-month course of
pulse methylprednisolone therapy in preserving renal
function. Adding a quarterly maintenance regimen to
monthly pulse cyclophosphamide therapy reduces the
rate of exacerbations. Plasmapheresis appears not to
enhance the effectiveness of prednisone and daily oral
cyclophosphamide. Small case series have shown
pulses of cyclophosphamide to be beneficial in patients
with lupus and neuropsychiatric disease refractory to
glucocorticoid therapy, acute pulmonary disease
(pneumonitis or hemorrhage), and thrombocytopenia.
Patients with systemic lupus erythematosus have an
increased prevalence of valvular and atherosclerotic
heart disease, apparently because of factors related to
the disease itself and to drug therapy.
• Conclusions: Cytotoxic agents are superior to glu-
cocorticoid therapy for the treatment of proliferative
lupus nephritis, but the optimal duration and intensity
of cytotoxic therapy remain undefined. Definitive stud-
ies of the treatment of autoimmune thrombocytopenia
and acute pulmonary disease and of the diagnosis and
treatment of neuropsychiatric disease are not available.
Ann Intern Med. 1995;122:940-950.
From the National Institutes of Health, Bethesda, Maryland. For
current author addresses, see end of text.
940 15 June 1995 • Annals of Internal Medicine • Volume 122 • Number 12
Oystemic lupus erythematosus is an extraordinarily com-
plex autoimmune disease that touches on nearly all med-
ical subspecialties (1). Evidence from a broad range of
basic science studies indicates that the pathogenesis of
this disease is equally complex and may vary from patient
to patient. The diverse expression of the common lupus
syndrome may result from variable abnormalities in inter-
secting genetic, immunologic, hormonal, and environmen-
tal pathways. Although many uncertainties about patho-
genic mechanisms remain, recent advances in diagnosis
and treatment have substantially improved the prognosis
of patients with systemic lupus erythematosus. As mortal-
ity rates decrease, issues such as comorbidity, complica-
tions of therapy, and overall quality of life are receiving
increased attention.
We discuss recent advances in systemic lupus erythem-
atosus. By necessity, this review is not comprehensive; we
focus on changing concepts and new information. In this,
the first part, we review issues related to the diagnosis
and management of systemic lupus erythematosus with
visceral involvement. In the second part, to be published
in the 1 July issue, we examine selected topics related to
dermatologic and joint disease, as well as issues related to
the antiphospholipid antibody syndrome, pregnancy, hor-
monal therapy, and morbidity and mortality. We conclude
with an overview of recent advances in the pathogenesis
of the disease.
Renal Disease
The kidney is the viscus most commonly affected by
systemic lupus erythematosus. With the use of sensitive
light, electron, and immunofluorescence microscopy, at
least modest abnormalities are seen in kidney biopsy spec-
imens from almost all patients with lupus. Approximately
75% of renal biopsy specimens reported in several series
have been classified as focal proliferative, diffuse prolifer-
ative, or membranous glomerulonephritis (2).
Pathogenesis
Localization of immune complexes in the kidney ap-
pears to be the inciting event for the development of
lupus nephritis. Autoantibodies that react with DNA and
other cellular components are characteristic of human and
murine systemic lupus erythematosus, but only a subset of
the resulting immune complexes seems to be nephro-
genic. Studies correlating the immunochemical properties
of autoantibodies with the type and severity of nephritis
have detected several features that may promote patho-
genicity, including quantity, charge, class, isotype, idio-
type, avidity for DNA, and efficiency of complement fix-
ation (3). Furthermore, cross-reactivity of anti-DNA
autoantibodies with glomerular cell surface antigens, as
well as with normal components of basement membrane
and mesangial matrix, probably promotes glomerular im-
mune complex formation and influences the location of
these deposits within the glomerulus (4). Thus, factors
that lead to the deposition of many proinflammatory im-
mune complexes in the subendothelial region of the glo-
merular capillary wall, adjacent to the circulation, are
likely to induce (through release of complement compo-
nents, cytokines, and other factors) cellular proliferation,
an inflammatory response, necrosis, and eventually fibro-
sis (5). Furthermore, a subset of autoantibodies may pen-
etrate glomerular cells, bind to nuclei, and contribute to
glomerular proliferation and proteinuria (6).
The subepithelial immune deposits characteristic of lu-
pus membranous nephropathy probably evolve through
the in situ interaction of autoantibodies with antigens,
such as DNA or histones, that bind to glomerular base-
ment membrane because of their affinity for basement
membrane components such as fibronectin, collagen,
laminin, and heparan sulfate (7). Subepithelial immune
complexes induce relatively little cellular proliferation or
inflammatory response. Glomerular capillary wall injury
appears to be induced by complement activation and for-
mation of the membrane attack complex, C5b-9, that has
been associated with this type of active immune complex-
mediated injury (8).
Diagnostic Studies
Laboratory Evaluation
Serologic variables have been extensively evaluated as
indicators of the activity of lupus nephritis. Serum com-
plement abnormalities have correlated with the degree of
renal histologic activity in several studies (9, 10). Persis-
tent C3 or CH 50 complement depression has been asso-
ciated with progression of kidney disease in some, but not
all, groups of patients (10-12). Antinuclear and anti-DNA
antibody levels have been less consistently related to fea-
tures of active glomerulonephritis (13). Serologic abnor-
malities may develop many months before evidence of
clinical renal involvement and should prompt close obser-
vation to detect changes in urinary sediment and protein
excretion rate, which are frequently considered stronger
indications for modifications of therapy.
Standard kidney function variables (such as serum cre-
atinine level and creatinine clearance) are insensitive in-
dicators of change in glomerular filtration rate and are
likely to underestimate the severity of glomerulonephritis
(14). More accurate assessments of glomerular filtration
rate are obtained by using inulin or iothalamate clear-
ances or by using creatinine clearance after blocking tu-
bular secretion of creatinine by cimetidine (15). Nonethe-
less, even these measures of kidney function may fail to
detect the extent of renal parenchymal injury because of
intrarenal hemodynamic compensatory mechanisms that
have been shown in animal models to augment filtration
in perfused glomeruli (16).
15 June 1995 • Annals of Internal Medicine • Volume 122 • Number 12
Renal Biopsy
A classic clinical syndrome (for example, rapidly pro-
gressive glomerulonephritis) may, in some cases, obviate
the need for a kidney biopsy to establish the type of lupus
nephritis. Many patients, however, present with clinical
features compatible with several of the classes of lupus
nephritis for which different treatment strategies are usu-
ally recommended. In these patients, renal biopsy data
may clarify an ambiguous situation and help to justify
various therapeutic options. In the absence of significant
proteinuria or urinary sediment abnormalities, we are
usually reluctant to recommend renal biopsy outside the
context of a research protocol.
Deliberations about treatment usually include an as-
sessment of prognosis. Hypertension has been associated
with renal disease progression and death (17). The con-
tribution of kidney morphologic evaluation to estimates of
prognosis has been debated vigorously. Detailed records
of the duration of nephritis (18) or the rate of change of
renal function (19) provide an indication of the balance of
reversible and irreversible injuries that may have oc-
curred. Kidney biopsy data provide a more direct ap-
praisal of the type of renal disease and have enhanced
outcome predictions based on clinical data in several ( 2 0 -
23), but not all (18, 24), studies. Variations in conclusions
may relate to the salutary effects of contemporary treat-
ments as well as to differences in patient selection criteria,
prognostic factors, and outcome measures studied. Sev-
eral investigators have observed the prognostic effect of
markedly active histologic features (such as cellular cres-
cents, fibrinoid necrosis, and subendothelial immune de-
posits) combined with chronic, irreversible morphologic
attributes (such as interstitial fibrosis, tubular atrophy,
and glomerular sclerosis) (22, 25, 26).
Treatment
Glucocorticoids
A mainstay of the treatment of systemic lupus erythem-
atosus, glucocorticoids are often used alone as initial ther-
apy for patients with lupus nephritis. Prednisone at low to
intermediate doses is usually sufficient for patients with
mesangial and mild focal proliferative glomerulonephritis.
Studies now in progress are evaluating the effectiveness
and toxicity of prednisone therapy given on alternate days
and of other treatment strategies for patients with mem-
branous lupus nephropathy (27).
Patients with diffuse proliferative or severe focal prolif-
erative glomerulonephritis are candidates for vigorous im-
munosuppressive treatments intended to control intrare-
nal inflammation. In some cases, this control can be
achieved by using daily, high-dose prednisone (1 mg/kg of
body weight daily) for approximately 2 months and then
tapering the dose to reduce the risk for glucocorticoid-
associated toxicities. The systemic effects of glucocorti-
coids are well recognized. High-dose glucocorticoids may
promote glomerular scarring by augmenting glomerular
capillary perfusion pressures (28) and by elevating low-
density lipoprotein (LDL) cholesterol levels, leading both
to enhanced mesangial cell uptake of oxidized LDL cho-
lesterol and to cellular injury (29).
Pulse intravenous methylprednisolone has been used as
an intensive initial therapy for patients with lupus nephri-
941
 theless, it has been recognized that intravenous pulse
cyclophosphamide treatments are complicated, costly, in-
convenient, uncomfortable, and potentially toxic.
Given these concerns, additional studies have been
done to address several questions. First, could an initial
intensive immunosuppressive regimen shorten the dura-
tion of treatment? Second, is there an advantage to sus-
tained immunosuppressive therapy for lupus nephritis?
And third, what are the long-term toxicities of intermit-
tent pulse cyclophosphamide therapy?
According to a recent study (39), exacerbations of ac-
tive renal and extrarenal disease are significantly more
likely to occur in patients receiving an intensive 6-month
course of pulse cyclophosphamide than in those receiving
a more sustained 30-month course (Figure 1). However,
pulse cyclophosphamide therapy may be associated with
substantial side effects. The risk for fatal opportunistic
infections of the pulmonary and central nervous systems
among patients with active systemic lupus erythematosus
treated with high-dose corticosteroids, cytotoxic drugs, or
both has been emphasized (40). Bladder cancer has been
seen in patients treated with daily oral cyclophosphamide
but has not been seen in our patients with lupus receiving
pulse cyclophosphamide therapy (35, 39), presumably be-
cause of the protective effects of hydration, a dilute di-
uresis, and mesna (2-mercaptoethanesulfonate). Hemato-
logic malignancies have been reported infrequently after
intravenous cyclophosphamide therapy for lupus nephritis
(41, 42). A large, multicenter study is needed to deter-
mine the effect of pulse cyclophosphamide therapy on the
risk for malignancy in patients with systemic lupus ery-
thematosus. Sustained amenorrhea was seen in 11 of 39
Figure 1. Treatment of severe lupus nephritis. Top. Probability of
not doubling serum creatinine levels in 65 patients with severe women younger than 40 years of age who were treated
active lupus nephritis randomly assigned to receive MP (intrave- with pulse cyclophosphamide therapy for systemic lupus
nous methylprednisolone, 1.0 g/m2 body surface area monthly for erythematosus (43). The risk for sustained amenorrhea is
6 months), CY-S (intravenous cyclophosphamide, 0.5 to 1.0 g/m2 significantly related to both the patient's age at the start
monthly for 6 months), or CY-L (intravenous cyclophosphamide, of pulse therapy and the number of doses of cyclophos-
0.5 to 1.0 g/m2 monthly for 6 months followed by quarterly
infusions for 24 months) (Gehan test comparing CY-L with MP, phamide received. These data, coupled with observations
P = 0.037). Bottom. Probability of no exacerbation of lupus about the risk for relapse after a short course of pulse
activity on completion of monthly pulses in groups randomly cyclophosphamide, pose a challenging problem. Recurring
assigned to receive CY-L and CY-S (Gehan test, P = 0.006). inflammation may result in sclerosing lesions that increase
Numbers of patients that remain at risk at various times are the risk for progressive renal failure during subsequent
shown along the abscissa. Reproduced with permission from
Boumpas and colleagues (39). episodes of active nephritis. A marked improvement in
renal status (resolution of initial elevations in serum cre-
atinine levels, low-grade proteinuria, and resolution of a
tis and other immune-mediated disorders. Favorable nephritic urinary sediment) favor a shortened course of
short-term results have been observed (19, 30), but this cytotoxic drug therapy (24). On the other hand, there is
therapy has been less extensively studied as a mainte- concern that discontinuing immunosuppressive therapy as
nance therapy for chronic disorders such as lupus nephri- soon as renal status is improved may increase the risk for
tis (31). The effectiveness and toxicity of daily high-dose relapse. Consequently, it has been recommended that pa-
oral prednisone and pulse intravenous methylpred- tients should receive quarterly pulse cyclophosphamide as
nisolone therapy have not been rigorously compared in maintenance therapy for approximately 1 year after
patients with lupus nephritis. achieving clinical renal remission, but this approach has
never been rigorously tested.
Cytotoxic Drugs
Immunosuppressive drug regimens that include cyto- Alternatives to this regimen of pulse cyclophosphamide
toxic drugs are more efficacious than prednisone alone in therapy are currently under investigation at the National
controlling clinical signs of active nephritis (32, 33), in Institutes of Health and other centers (44). That more
preventing renal scarring (34), and ultimately in reducing consistent and rapid responses could be achieved by com-
the risk for end-stage renal failure, but they have not bining pulse cyclophosphamide and pulse methylpred-
been shown to be more effective in reducing the risk for nisolone therapies or by synchronizing pulse cyclophos-
death (35, 36). Among cytotoxic drug regimens, intermit- phamide therapy and plasmapheresis has been suggested
tent pulse cyclophosphamide therapy appears to have one (45). Plasmapheresis appears not to enhance the effec-
of the most favorable therapeutic indexes (35-38). None- tiveness of prednisone and daily oral cyclophosphamide

942 15 June 1995 • Annals of Internal Medicine • Volume 122 • Number 12

(46). Other experimental immunosuppressive regimens,
including total lymphoid irradiation (47) and cyclosporine
(48, 49), have been described but have not been prospec-
tively compared with other options. There is particular
interest in the development of more targeted treatments
involving monoclonal antibodies and biologic-response
modifiers; these are emerging as products of basic re-
search (50, 51).
Neuropsychiatric Disease
Neuropsychiatric symptoms are common in patients
with systemic lupus erythematosus and can be separated
into primary events, which result directly from immune-
mediated injury to the central nervous system, and sec-
ondary events, which result from disease in other organs,
complications of therapy, or both (Table 1) (52-55). Pri-
mary neuropsychiatric events (neuropsychiatric lupus) typ-
ically occur in a setting of clinical or serologic evidence of
active systemic lupus erythematosus. Although relatively
uncommon, systemic lupus erythematosus may first
present with neurologic disease and should be included in
the differential diagnosis of neuropsychiatric symptoms,
especially when these occur in young patients (54).
Pathogenesis
Multifocal cerebral cortical microinfarctions associated
with microvascular injury are the predominant histopatho-
logic abnormalities attributed to neuropsychiatric lupus;
vasculitis is rare (56). The leading hypothesis about the
pathogenesis of neuropsychiatric lupus invokes vascular
occlusion because of vasculopathy, vasculitis (in rare cas-
es), leukoagglutination or thrombosis, and antibody-medi-
ated neuronal cell injury or dysfunction. Antibodies may
be produced intrathecally or may gain access to the cen-
tral nervous system from a blood-brain barrier disturbed
by the vascular injury (Table 1).
Clinical Presentation
All parts of the nervous system (central, peripheral, or
autonomic) may be involved (Table 2) (53). There are
Table 1. Pathogenesis of Neuropsychiatric Events in Pa-
tients with Systemic Lupus Erythematosus*
Primary events
Vascular occlusion from immune-complex-mediated or
antibody (for example, antiphospholipid) -mediated
vasculopathy, vasculitis, leukoagglutination, or thrombosis.
Cerebral dysfunction from antibodies to brain tissue!
(antineuronal, antiribosomal P protein) or cytokines
(interleukin-6, interferon-a).
Secondary events
Infection (meningitis, abscess, discitis)
Cerebrovascular accidents due to accelerated atherosclerosis
Hypertensive encephalopathy
Metabolic encephalopathy (uremia, electrolyte imbalance,
fever, hypoxia)
Hypercoagulable state due to the nephrotic syndrome
Drugs (glucocorticoids, nonsteroidal anti-inflammatory agents,
trimethoprim and sulfamethoxazole, hydroxychloroquine,
azathionrineV
* Adapted from references 52-55.
t Intrathecal production or entrance through a blood-brain barrier dis-
turbed by vascular injury.
15 June 1995 • Annals of Internal Medicine • Volume 122 • Number 12
Table 2. Major Neuropsychiatric Manifestations of Sys-
temic Lupus Erythematosus*
Diffuse cerebral dysfunction
Organic brain syndrome (20%)
Psychosis (10%)
Major affective disorder (< 1%)
Focal cerebral dysfunction
Seizures, all types (15%)
Cerebrovascular accidents (5%)
Transverse myelitis (1%)
Movement disorder
Chorea (3%)
Athetosis (rare)
Parkinson-like (rare)
Cerebellar ataxia (rare)
Peripheral neuropathy
Symmetric sensorimotor (10%)
Mononeuritis multiplex (rare)
Guillain-Barre syndrome (extremely rare)
Autonomic neuropathy (extremely rare)
Miscellaneous
Aseptic meningitis (rare)
Pseudotumor cerebri (rare)
Cerebral venous thrombosis (extremely rare)
* Adapted from references 52-55. Numbers in parentheses indicate
approximate prevalence.
many neuropsychiatric manifestations of systemic lupus
erythematosus; the organic brain syndrome has received
increased attention in recent years and is discussed here
briefly.
Organic Brain Syndrome
This syndrome usually manifests with various degrees of
memory impairment, apathy, and loss of orientation, in-
tellect or judgment, but agitation, delirium, stupor, or
coma may occur in severe cases. Symptomatic organic
brain syndrome has been reported in as many as 20% of
patients with systemic lupus erythematosus (55). Limited
cognitive impairment has been reported in 20% to 70%
of these patients when examined using formal neuropsy-
chologic testing (55, 57) and may occur independently of
other manifestations of neuropsychiatric lupus or systemic
disease activity (58, 59). Slow but progressive deteriora-
tion may occur in a few patients and results in severe,
debilitating dementia. Dementia may be caused by active
ongoing neuropsychiatric lupus or may result from previ-
ous insult to the central nervous system or from multiple
infarctions caused by antiphospholipid antibodies (55, 60).
Diagnostic Studies
Analysis of the cerebrospinal fluid is one of the most
helpful diagnostic studies. Although elevated cell counts,
protein levels, or both are found in only about one third
of patients, analysis of the cerebrospinal fluid helps ex-
clude acute or chronic infectious meningitis. Elevated in-
trathecal IgG, IgM, or IgA indices (or a combination of
these) and oligoclonal bands have been seen in patients
with diffuse neuropsychiatric disease but are not specific
to neuropsychiatric lupus (55). More specialized tests,
such as measurements of interleukin-6 and interferon-a,
are not readily available in most places (54).
943

Figure 2. Magnetic resonance imaging in neuropsychiatric lupus.
Left. Axial T2-weighted scan of the brain in a woman 24 years of
age with systemic lupus erythematosus. Small foci of increased
signal intensity are identified at the periventricular area of the
white matter (arrows). These lesions are caused by microvascular
injury in the peripheral branches of the cerebral arteries resulting
in ischemia, edema, and infarction. If the underlying process
persists, these lesions may increase in number and coalesce,
forming larger lesions. In contrast to the smaller lesions, these
larger lesions may also be detected as hypodense areas on com-
puted tomographic scans. Right. Axial T2-weighted scan shows
increased signal intensity in the gray matter of the left basal
ganglia. Abnormalities of the cortical or the deep gray matter are
usually due to involvement of more proximal branches of the
cerebral arteries, resulting in edema with high-signal intensity on
T2-weighted and proton density images. These lesions may re-
solve spontaneously or with therapy or may progress to infarc-
tion, in which case they may also be detected by computed
tomographic scanning. In this patient, similar lesions were also
seen in the left cerebral peduncle and in the cervical spinal cord.
After treatment with oral glucocorticoids and pulses of cyclo-
phosphamide, these lesions resolved within approximately 6
months (Reproduced with permission from Boumpas and col-
leagues [71]).
Autoantibodies
Antineuronal antibodies are present in the serum of as
many as 75% of patients with systemic lupus erythemato-
sus and neuropsychiatric lupus (53). Similarly, antiriboso-
mal P protein antibodies have been found in 45% to 90%
of patients with systemic lupus erythematosus and psycho-
sis or major depression in most (61), but not all (62),
studies. These autoantibodies may be found in as many as
25% of unselected patients with systemic lupus erythem-
atosus, and thus their presence must be interpreted with
caution (55). Antineuronal antibodies and antiribosomal
P protein antibodies are more likely to be seen in patients
with diffuse rather than focal central nervous system in-
volvement. This suggests that the former may be autoan-
tibody mediated (53, 55).
The specific antigens that induce the antineuronal an-
tibodies are beginning to be identified. Hanson and col-
leagues (63) described a 50-kd antigen in the plasma
membrane of brain synaptic terminals (neuronal compart-
ments vital for normal brain function) that bound anti-
bodies present in the sera of 19 of 20 patients with
neuropsychiatric lupus. Antiribosomal P protein antibod-
ies were initially found to be directed to cytoplasmic
(ribosomal) proteins. More recently, however, reactive P
peptides have also been found on the cell surface; this
suggests that these autoantibodies may directly affect the
function and viability of cells that express this antigenic
target (64). In case-control studies, anticardiolipin anti-
bodies have been associated with specific neuropsychiatric
944 15 June 1995 • Annals of Internal Medicine • Volume 122 • Number 12
features, including cerebrovascular accidents, multi-infarc-
tion dementia, seizures, intracranial arterial and venous
thrombosis, chorea, and acute transverse myelitis (60, 65).
With the exception of cerebrovascular accidents, the as-
sociation between these syndromes and antiphospholipid
antibodies has not been firmly established.
Neuroimaging Studies
Magnetic resonance imaging shows greater contrast and
detail than computed tomography, but it also shows more
clinically silent abnormalities and incidental findings (66).
Computed tomography is sufficient for the initial diagno-
sis of most mass lesions and of intracranial hemorrhage
demanding immediate intervention, and it requires less
patient cooperation than magnetic resonance imaging (67).
The findings of magnetic resonance imaging in neuro-
psychiatric lupus reflect the underlying histopathologic
findings of vascular injury and may involve the white
or gray matter of the brain parenchyma (Figure 2). In
general, patients with focal neurologic findings or focal
seizures are more likely than patients with diffuse involve-
ment to have abnormalities detected by magnetic reso-
nance imaging. In most cases, this imaging cannot distin-
guish between primary and secondary neuropsychiatric
events. It is also impossible to establish a diagnosis of
neuropsychiatric lupus from neuroimaging studies in the
absence of clinical history. Furthermore, in many cases,
the correlation between magnetic resonance imaging find-
ings and clinical presentation is poor. For example, inter-
pretation of white matter abnormalities (which are often
clinically silent) is problematic because their prevalence in
patients with nonsystemic lupus erythematosus increases
from 20% in persons younger than 50 years of age to
90% in persons older than 70 years of age (66).
Single-photon emission computed tomography has been
used by several investigators to show a higher prevalence
of abnormal cortical perfusion in patients with neuropsy-
chiatric lupus than in patients with systemic lupus ery-
thematosus and no neuropsychiatric symptoms (68). Un-
fortunately, quantitative, rigorous assessments of the
clinical utilities of magnetic resonance imaging and single-
photon emission computed tomography have not been
done in large case series or well-controlled comparison
trials. Furthermore, data on the diagnostic accuracy of,
the diagnostic and therapeutic effect of, and the change in
patient outcomes attributable to these tests are not avail-
able (66, 69).
Management
Therapy for neuropsychiatric lupus differs according to
the type of presentation, its severity, and the nature of the
underlying process (for example, inflammatory or throm-
botic). Unfortunately, decisions about immunosuppressive
therapy must currently be made in the absence of data
from randomized controlled studies (54). Glucocorticoids
remain the first line of therapy for the major manifesta-
tions of neuropsychiatric lupus. In patients with severe
disease or in those who do not respond to standard
prednisone therapy, pulse methylprednisolone therapy
may be helpful. Small case series (45, 70-72) have shown
intravenous pulses of cyclophosphamide to be useful in
patients with very severe disease (for example, those with
strokes, cerebritis, acute transverse myelitis, and coma), in
those who fail to respond to glucocorticoids, and in those
who relapse while glucocorticoid therapy is being tapered.
Plasmapheresis and intravenous immunoglobulin have
also been proposed as adjunct therapies for life-threaten-
ing neuropsychiatric lupus, but only on the basis of case
reports. In patients with thrombosis of intracerebral ves-
sels (for example, cerebral vein thrombosis), and in the
absence of generalized lupus activity or high-grade cere-
brospinal fluid abnormalities, therapy should be based
predominantly on anticoagulation (54). The role of im-
munosuppressive therapy in these cases is not clear.
Cardiac Disease
Cardiovascular involvement has been receiving in-
creased attention in patients with systemic lupus erythem-
atosus. Recent prospective studies using advanced diag-
nostic methods have allowed the delineation of the
prevalence and significance of discrete cardiac manifesta-
tions such as valvular disease, myocardial dysfunction, and
pericardial disease (73-77). In other studies (78, 79), cor-
onary artery disease has been found to have a substantial
effect on mortality and morbidity in patients with systemic
lupus erythematosus; it accounts for as many as one third
of all deaths seen in this population (78, 79).
Valvular Heart Disease
The spectrum of lupus-related valvulopathies has been
expanded to include valve leaflet thickening with or with-
out valve dysfunction (regurgitation or stenosis) in addi-
tion to the more characteristic valve lesions of Libman-
Sacks endocarditis (nonbacterial verrucous endocarditis)
(73). The prevalence of lupus-associated valvulopathy
ranges from 18% to 74% depending on the cohort of
patients studied, the duration of the disease, and the
mode of diagnosis (for example, autopsy studies or trans-
thoracic or transesophageal echocardiography) (73, 76,
80). Valvular abnormalities may progress to hemodynam-
ically significant lesions that require valve replacement
(73, 81). Furthermore, an increased risk for infectious
endocarditis has been reported in retrospective reviews of
patients with systemic lupus erythematosus (82, 83). Be-
cause valvular lesions (such as Libman-Sacks endocardi-
tis) may be overlooked by echocardiography and do not
necessarily correlate with physical examination findings,
some have suggested that antibiotic prophylaxis be con-
sidered for all patients with systemic lupus erythematosus
having dental or surgical procedures (84, 85), but this
recommendation has not been widely accepted.
The pathogenesis of valvular heart disease in systemic
lupus erythematosus is unknown, but contributing factors
may include verrucous vegetations, fibrinoid degeneration
of valve cusps, valvulitis, fibrotic scarring (possibly wors-
ened by glucocorticoids), vasculitis, or rupture of chorda
tendineae (81). The relation between antiphospholipid
antibodies and the development of cardiac valvular ab-
normalities is controversial. Valvular lesions have been
seen with increased frequency in patients with the primary
antiphospholipid syndrome and in patients with systemic
lupus erythematosus and antiphospholipid antibodies (86-
15 June 1995 • Annals of Internal Medicine • Volume 122 • Number 12
Table 3. Primary Respiratory System Involvement In Sys-
temic Lupus Erythematosus*
Upper airway disease
Epiglottitis
Subglottic stenosis
Vocal cord paralysis
Laryngeal edema or ulceration
Inflammatory mass lesions or nodules
Cricoarytenoid arthritis
Necrotizing vasculitis
Parenchymal disease
Acute lupus pneumonitis
Alveolar hemorrhage syndrome
Chronic lupus pneumonitis or interstitial lung disease
Lymphocytic interstitial pneumonia or pseudolymphoma
Bronchiolitis obliterans with or without organizing pneumonia
Respiratory muscle disease
Shrinking lung syndrome
Pleural disease
Pleuritis with or without effusion
Vascular disease
Pulmonary hypertension
Pulmonary embolism
Acute reversible hypoxemia
* Adapted from references 93-98.
88); this has led to speculation about a possible causal
relation (80). However, valvular abnormalities are also
seen in patients with systemic lupus erythematosus who
lack antiphospholipid antibodies; this suggests that addi-
tional pathogenetic factors may be operative in the devel-
opment of endocardial lesions in patients with systemic
lupus erythematosus (76, 89).
Accelerated Atherosclerosis
Atherosclerosis is emerging as a significant cause of
death and illness in patients with systemic lupus erythem-
atosus. The mortality rate from coronary artery disease in
patients with systemic lupus erythematosus is estimated to
be ninefold greater than predicted population-based rates
(90). Severe atherosclerotic narrowing of coronary arter-
ies has been well documented on autopsy studies, even in
patients younger than 35 years of age.
Although the pathogenesis of accelerated atherosclero-
sis is unknown, it is believed to be multifactorial. Tradi-
tional cardiac risk factors, such as hypertension, obesity,
and hyperlipidemia, are observed with high frequency in
patients with systemic lupus erythematosus. Fifty-three
percent of these patients have three or more risk factors;
this prevalence greatly exceeds the prevalence seen in a
matched population (78). Glucocorticoid-induced dysli-
poproteinemia (91) and complications that result from
disease involvement in other organ systems (for example,
renal disease leading to hypertension and hyperlipidemia)
may also potentiate the atherosclerotic process. Circulat-
ing immune complexes may promote intracellular choles-
terol accumulation and therefore may be an additional
compounding factor (92).
Pulmonary Disease
The involvement of the respiratory system in systemic
lupus erythematosus is relatively common, and its clinical
manifestations are diverse (Table 3). Primary pulmonary
945

Figure 3. Computed tomographic scan of the lung in a patient
with systemic lupus erythematosus and interstitial pneumonia.
This patient presented with several weeks of dry cough and
dyspnea on exertion. Note the bilateral ground-glass opacities
that do not obscure underlying vessels (6-mm axial section
through lung bases). Open lung biopsy showed lymphocytic in-
terstitial pneumonia with numerous germinal centers situated
adjacent to bronchial epithelium and a less prominent inflamma-
tory background of lymphocytes and plasma cells within the
alveolar septae. These abnormalities resolved after therapy with
high-dose glucocorticoids.
involvement caused by systemic lupus erythematosus may
follow a variable course from incidental abnormalities
noted on chest radiography or pulmonary function testing
to acute or chronic disease. Acute pulmonary disease
tends to develop in association with generalized lupus
activity, whereas chronic pulmonary involvement may
progress independently of disease activity in other organs.
Acute Pulmonary Disease
Acute Lupus Pneumonitis and Alveolar Hemorrhage
Alveolar hemorrhage and acute lupus pneumonitis are
uncommon, life-threatening syndromes associated with
systemic lupus erythematosus; they result from acute in-
jury to the alveolar-capillary unit (99). Acute lupus pneu-
monitis is characterized by the abrupt onset of fevers,
dyspnea with hypoxemia, and patchy alveolar infiltrates on
chest radiography, without evidence of an underlying in-
fection. The alveolar hemorrhage syndrome, which is less
common than acute lupus pneumonitis, has a similar pre-
sentation, except that it is associated with an acute de-
cline in hemoglobin levels caused by bleeding within the
lung (99).
Although they have not been the subject of prospective
controlled studies, glucocorticoids are generally accepted
as the first line of therapy for acute immune-mediated
lung injury in patients with systemic lupus erythematosus.
Pulse methylprednisolone therapy seems to be effective in
treating various immune-mediated pulmonary hemorrhage
syndromes (100). The addition of azathioprine or cyclo-
phosphamide is generally advocated in patients who are
critically ill or unresponsive to glucocorticoids (101). Plas-
mapheresis as an adjunct to immunosuppressive therapy
has been used in rapidly deteriorating patients (45). Ther-
apy must be initiated expeditiously because these syn-
dromes can accelerate rapidly, leading to respiratory fail-
ure and death. Overall mortality rates for both syndromes
946 15 June 1995 • Annals of Internal Medicine • Volume 122 • Number 12
are high, ranging from 50% to 90% despite treatment (93,
102). However, a recent case series of patients with sys-
temic lupus erythematosus and pulmonary hemorrhage
suggested that the prognosis for these patients may not be
as grim as was previously thought and that early diagnosis
combined with aggressive immunosuppression may favor-
ably affect survival rates (102).
Acute Reversible Hypoxemia
A newly described syndrome of acute reversible hypox-
emia has been reported in a subpopulation of acutely ill
patients with systemic lupus erythematosus (94). The ex-
act pathogenesis of this syndrome is unclear. It has been
postulated that the elevated levels of complement split
products detected in the plasma of these patients may
activate circulating neutrophils, which aggregate within
the pulmonary vasculature, and partly account for the
observed diminished oxygenation capacity. In this series,
hypoxemia resolved and the level of complement split
products decreased after treatment with glucocorticoids
for extrapulmonary disease manifestations.
Chronic Pulmonary Disease
Interstitial Lung Disease
Chronic interstitial lung disease may develop as a con-
sequence of acute pneumonitis or as an independent
manifestation of systemic lupus erythematosus (99, 103).
Radiographic findings of interstitial lung disease may be
more common than symptoms. Discriminating between
inflammatory alveolitis (which is treatable) and chronic
fibrosis is the primary difficulty in determining the appro-
priate therapeutic approach to chronic lupus pneumonitis.
Bronchoalveolar lavage and gallium scanning were used
to evaluate interstitial lung disease in the past, but their
correlation with disease activity or potential therapeutic
response has been questioned. High-resolution computed
tomography is emerging as an important noninvasive tool
in the evaluation of idiopathic pulmonary fibrosis because
high-resolution computed tomographic patterns (such as a
ground-glass appearance that suggests active inflammation
or a reticular pattern with honeycombing that suggests
irreversible fibrosis) have been shown to correlate with
histologic findings on open lung biopsy and with response
to therapy (104-106) (Figure 3). Although this has not
been critically examined in interstitial lung disease asso-
ciated with systemic lupus erythematosus, high-resolution
computed tomographic scans with a pattern that suggests
chronic fibrosis may help to avoid unnecessary immuno-
suppression.
Pulmonary Hypertension
Increasingly recognized as a complication of systemic
lupus erythematosus, pulmonary hypertension in this con-
dition closely resembles primary idiopathic pulmonary hy-
pertension. The Raynaud phenomenon has been seen in
as many as 75% of patients with systemic lupus erythem-
atosus and pulmonary hypertension and in only 25% of
the general population with systemic lupus erythematosus
(107). Serologic testing shows a high incidence of antiri-
bonucleoprotein antibodies, rheumatoid factor, and an-
tiphospholipid antibodies (107). The pathogenesis of pul-
monary hypertension associated with systemic lupus
erythematosus is unknown, but the condition is believed
to result from vascular occlusion caused by vasoconstric-
tion, vasculopathy or vasculitis, platelet aggregation or
thrombosis, and parenchymal lung disease (93, 107, 108).
Currently, no therapy has been proved efficacious for the
treatment of pulmonary hypertension associated with ei-
ther idiopathic or systemic lupus erythematosus. Prognosis
is poor, and a steady decline in pulmonary function, de-
spite treatment, is usual (109). Although it has been little
studied, heart-lung transplantation may be an option in
patients with systemic lupus erythematosus, advanced pul-
monary hypertension, and minimal disease activity in
other organs (109, 110).
Hematologic Disease: Autoimmune Thrombocytopenia
Autoimmune thrombocytopenia occurs in as many as
25% of patients with systemic lupus erythematosus, and it
may be severe (platelet count less than 20 X 109/L) in
approximately 5% of these patients. A positive test result
for antinuclear antibodies has been reported to occur in
as many as 30% of patients with chronic idiopathic
thrombocytopenic purpura, and this may present diagnos-
tic and therapeutic problems (111). The presence of high-
titer antinuclear antibodies in combination with antibod-
ies to extractable nuclear antigens (for example, Ro/SS-A,
La/SS-B, ribonucleoprotein, or Smith) or anti-double-
stranded DNA antibodies increases the likelihood that
additional manifestations of systemic lupus erythematosus
will develop at some future date (112).
Pathogenesis and Clinical Presentation
Elevated platelet-associated IgG is found in patients
with systemic lupus erythematosus with and without
thrombocytopenia. It is not clear whether this indicates
platelet-specific antibody or adsorbed immune complexes
(111). Antiplatelet autoantibodies bind to one or more
surface glycoproteins (usually the glycoprotein Ilb-IIIa
complex). The antibody-coated platelets are ingested by
macrophages of the spleen, liver, lymph nodes, and bone
marrow, which carry receptors for the Fc region of im-
munoglobulin. Phagocytosis is more efficient when the
antiplatelet antibodies belong to the IgGx and IgG 2 sub-
types (113). Antibodies to specific target antigens (other
than the glycoprotein Ilb-IIIa complex) on platelets of
patients with systemic lupus erythematosus and thrombo-
cytopenia have also been described (114). Several studies
have documented an association between the develop-
ment of thrombocytopenia and the presence of antiphos-
pholipid antibodies (115). Other case reports (116) have
suggested an association between systemic lupus erythem-
atosus and a syndrome similar to thrombotic thrombocy-
topenic purpura. It is difficult to differentiate between
thrombotic thrombocytopenic purpura and the cata-
strophic occlusion syndrome in patients with antiphospho-
lipid antibody. Patients with thrombocytopenia are at in-
creased risk for bleeding either spontaneously or after
trauma. Spontaneous bleeding is rare unless the platelet
count is less than 5 X 109/L, an associated congenital or
acquired defect in platelet function is present, or a co-
agulopathy is present (117, 118). Although thrombocyto-
penia rarely causes a fatal hemorrhage in patients with
systemic lupus erythematosus, it may be a marker of more
15 June 1995 • Annals of Internal Medicine • Volume 122 • Number 12
aggressive and severe disease and has a substantial nega-
tive effect on the prognosis of systemic lupus erythema-
tosus (79).
Treatment
Randomized controlled studies of therapy for autoim-
mune thrombocytopenia are not available, and treatment
is based on extrapolation from studies of patients with
idiopathic thrombocytopenic purpura and small case se-
ries in patients with systemic lupus erythematosus. Ther-
apy is aimed at attaining a complete and lasting response.
If this is unsuccessful, subsequent therapy should be di-
rected toward maintaining "safe" platelet counts (20 X
109/L) (117). Therapy may not be necessary in patients
with no evidence of systemic lupus erythematosus activity
in other organs, a platelet count of more than 20 to 30 X
109/L, and no evidence of coexisting coagulopathy or
platelet dysfunction. For all other patients, glucocorticoids
are usually recommended as initial treatment. A random-
ized clinical trial in children and adults with acute idio-
pathic thrombocytopenic purpura showed similar efficacy
for low-dose (0.25 mg/kg daily) and high-dose (1.0 mg/kg
daily) glucocorticoids (prednisone or prednisolone) (119).
Patients who fail glucocorticoid therapy or relapse during
tapering may benefit from splenectomy, danazol, intrave-
nous immunoglobulin, vinca alkaloids, or intermittent
pulses of methylprednisolone, dexamethasone, or cyclo-
phosphamide (111, 120-123). Pulse cyclophosphamide
therapy is particularly attractive in patients with attendant
involvement of other organs (such as the kidneys, the
central nervous system, and the lungs) (123). For patients
with severe refractory idiopathic thrombocytopenic pur-
pura, combination chemotherapy with cyclophosphamide
and prednisone combined with either vincristine, vincris-
tine and procarbazine, or etoposide has been reported to
be beneficial in a case series of 10 patients (124).
Acknowledgments: The authors thank Drs. John L. Decker, Alfred D.
Steinberg, and Paul H. Plotz for their leadership in planning and imple-
menting studies of systemic lupus erythematosus at the National Institutes
of Health; Dr. Nicholas J. Patronas for invaluable assistance and useful
comments in the discussion of neuroimaging studies in patients with sys-
temic lupus erythematosus; Dr. Catherine K. Chow for useful discussions
on the role of computed tomography in the diagnosis of pulmonary
disease; Drs. W. Travis and C.L. Phillips for their assistance with the
interpretation of the pathology of Figure 3; and Ms. Lisa A. Miller and
Mr. Andrew S. Lerner for manuscript preparation.
Requests for Reprints: Dimitrios T. Boumpas, MD, National Institutes of
Health, Building 10, Room 3N-112, Bethesda, MD 20892.
Current Author Addresses: Drs. Boumpas, Austin, and Fessler: National
Institutes of Health, Building 10, Room 3N-112, Bethesda, MD 20892-
1268.
Dr. Balow: National Institutes of Health, Building 10, Room 9N-222,
Bethesda, MD 20892-1818.
Dr. Klippel: National Institutes of Health, Building 10, Room 9S-205,
Bethesda, MD 20892-1828.
Dr. Lockshin: National Institutes of Health, Building 31, Room 4C-32,
Bethesda, MD 20892-2350.
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