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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 Oystemic lupus erythematosus is an extraordinarily com-
the diagnosis and management of systemic lupus ery- plex autoimmune disease that touches on nearly all med-
thematosus with visceral involvement (renal, neuropsy- ical subspecialties (1). Evidence from a broad range of
chiatric, cardiopulmonary, and hematologic disease). basic science studies indicates that the pathogenesis of
• Data Sources and Study Selection: Review of the this disease is equally complex and may vary from patient
English-language medical literature with emphasis on to patient. The diverse expression of the common lupus
articles published in the last 5 years. More than 400 syndrome may result from variable abnormalities in inter-
articles were reviewed. secting genetic, immunologic, hormonal, and environmen-
• Dafa Synthesis: Recent debates pertaining to lupus tal pathways. Although many uncertainties about patho-
nephritis have focused on the value of kidney biopsy genic mechanisms remain, recent advances in diagnosis
data and the role of cytotoxic drug therapies. Many and treatment have substantially improved the prognosis
studies have shown that estimates of prognosis are of patients with systemic lupus erythematosus. As mortal-
enhanced by consideration of clinical, demographic, ity rates decrease, issues such as comorbidity, complica-
and histologic features. For patients with severe lupus tions of therapy, and overall quality of life are receiving
nephritis, an extended course of pulse cyclophospha- increased attention.
mide therapy is more effective than a 6-month course of We discuss recent advances in systemic lupus erythem-
pulse methylprednisolone therapy in preserving renal atosus. By necessity, this review is not comprehensive; we
function. Adding a quarterly maintenance regimen to focus on changing concepts and new information. In this,
monthly pulse cyclophosphamide therapy reduces the the first part, we review issues related to the diagnosis
rate of exacerbations. Plasmapheresis appears not to and management of systemic lupus erythematosus with
enhance the effectiveness of prednisone and daily oral visceral involvement. In the second part, to be published
cyclophosphamide. Small case series have shown in the 1 July issue, we examine selected topics related to
pulses of cyclophosphamide to be beneficial in patients dermatologic and joint disease, as well as issues related to
with lupus and neuropsychiatric disease refractory to the antiphospholipid antibody syndrome, pregnancy, hor-
glucocorticoid therapy, acute pulmonary disease monal therapy, and morbidity and mortality. We conclude
(pneumonitis or hemorrhage), and thrombocytopenia. with an overview of recent advances in the pathogenesis
Patients with systemic lupus erythematosus have an of the disease.
increased prevalence of valvular and atherosclerotic
heart disease, apparently because of factors related to
the disease itself and to drug therapy. Renal Disease
• Conclusions: Cytotoxic agents are superior to glu- The kidney is the viscus most commonly affected by
cocorticoid therapy for the treatment of proliferative systemic lupus erythematosus. With the use of sensitive
lupus nephritis, but the optimal duration and intensity light, electron, and immunofluorescence microscopy, at
of cytotoxic therapy remain undefined. Definitive stud- least modest abnormalities are seen in kidney biopsy spec-
ies of the treatment of autoimmune thrombocytopenia imens from almost all patients with lupus. Approximately
and acute pulmonary disease and of the diagnosis and 75% of renal biopsy specimens reported in several series
treatment of neuropsychiatric disease are not available. 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
Ann Intern Med. 1995;122:940-950. the resulting immune complexes seems to be nephro-
genic. Studies correlating the immunochemical properties
From the National Institutes of Health, Bethesda, Maryland. For of autoantibodies with the type and severity of nephritis
current author addresses, see end of text. have detected several features that may promote patho-
Laboratory Evaluation
Serologic variables have been extensively evaluated as Treatment
indicators of the activity of lupus nephritis. Serum com- Glucocorticoids
plement abnormalities have correlated with the degree of A mainstay of the treatment of systemic lupus erythem-
renal histologic activity in several studies (9, 10). Persis- atosus, glucocorticoids are often used alone as initial ther-
tent C3 or CH 50 complement depression has been asso- apy for patients with lupus nephritis. Prednisone at low to
ciated with progression of kidney disease in some, but not intermediate doses is usually sufficient for patients with
all, groups of patients (10-12). Antinuclear and anti-DNA mesangial and mild focal proliferative glomerulonephritis.
antibody levels have been less consistently related to fea- Studies now in progress are evaluating the effectiveness
tures of active glomerulonephritis (13). Serologic abnor- and toxicity of prednisone therapy given on alternate days
malities may develop many months before evidence of and of other treatment strategies for patients with mem-
clinical renal involvement and should prompt close obser- branous lupus nephropathy (27).
vation to detect changes in urinary sediment and protein Patients with diffuse proliferative or severe focal prolif-
excretion rate, which are frequently considered stronger erative glomerulonephritis are candidates for vigorous im-
indications for modifications of therapy. munosuppressive treatments intended to control intrare-
Standard kidney function variables (such as serum cre- nal inflammation. In some cases, this control can be
atinine level and creatinine clearance) are insensitive in- achieved by using daily, high-dose prednisone (1 mg/kg of
dicators of change in glomerular filtration rate and are body weight daily) for approximately 2 months and then
likely to underestimate the severity of glomerulonephritis tapering the dose to reduce the risk for glucocorticoid-
(14). More accurate assessments of glomerular filtration associated toxicities. The systemic effects of glucocorti-
rate are obtained by using inulin or iothalamate clear- coids are well recognized. High-dose glucocorticoids may
ances or by using creatinine clearance after blocking tu- promote glomerular scarring by augmenting glomerular
bular secretion of creatinine by cimetidine (15). Nonethe- capillary perfusion pressures (28) and by elevating low-
less, even these measures of kidney function may fail to density lipoprotein (LDL) cholesterol levels, leading both
detect the extent of renal parenchymal injury because of to enhanced mesangial cell uptake of oxidized LDL cho-
intrarenal hemodynamic compensatory mechanisms that lesterol and to cellular injury (29).
have been shown in animal models to augment filtration Pulse intravenous methylprednisolone has been used as
in perfused glomeruli (16). an intensive initial therapy for patients with lupus nephri-
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-
Figure 2. Magnetic resonance imaging in neuropsychiatric lupus. sis of most mass lesions and of intracranial hemorrhage
Left. Axial T2-weighted scan of the brain in a woman 24 years of demanding immediate intervention, and it requires less
age with systemic lupus erythematosus. Small foci of increased patient cooperation than magnetic resonance imaging (67).
signal intensity are identified at the periventricular area of the The findings of magnetic resonance imaging in neuro-
white matter (arrows). These lesions are caused by microvascular
injury in the peripheral branches of the cerebral arteries resulting psychiatric lupus reflect the underlying histopathologic
in ischemia, edema, and infarction. If the underlying process findings of vascular injury and may involve the white
persists, these lesions may increase in number and coalesce, or gray matter of the brain parenchyma (Figure 2). In
forming larger lesions. In contrast to the smaller lesions, these general, patients with focal neurologic findings or focal
larger lesions may also be detected as hypodense areas on com-
puted tomographic scans. Right. Axial T2-weighted scan shows seizures are more likely than patients with diffuse involve-
increased signal intensity in the gray matter of the left basal ment to have abnormalities detected by magnetic reso-
ganglia. Abnormalities of the cortical or the deep gray matter are nance imaging. In most cases, this imaging cannot distin-
usually due to involvement of more proximal branches of the guish between primary and secondary neuropsychiatric
cerebral arteries, resulting in edema with high-signal intensity on
T2-weighted and proton density images. These lesions may re- events. It is also impossible to establish a diagnosis of
solve spontaneously or with therapy or may progress to infarc- neuropsychiatric lupus from neuroimaging studies in the
tion, in which case they may also be detected by computed absence of clinical history. Furthermore, in many cases,
tomographic scanning. In this patient, similar lesions were also the correlation between magnetic resonance imaging find-
seen in the left cerebral peduncle and in the cervical spinal cord. ings and clinical presentation is poor. For example, inter-
After treatment with oral glucocorticoids and pulses of cyclo-
phosphamide, these lesions resolved within approximately 6 pretation of white matter abnormalities (which are often
months (Reproduced with permission from Boumpas and col- clinically silent) is problematic because their prevalence in
leagues [71]). 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).
Autoantibodies Single-photon emission computed tomography has been
Antineuronal antibodies are present in the serum of as used by several investigators to show a higher prevalence
many as 75% of patients with systemic lupus erythemato- of abnormal cortical perfusion in patients with neuropsy-
sus and neuropsychiatric lupus (53). Similarly, antiriboso- chiatric lupus than in patients with systemic lupus ery-
mal P protein antibodies have been found in 45% to 90% thematosus and no neuropsychiatric symptoms (68). Un-
of patients with systemic lupus erythematosus and psycho- fortunately, quantitative, rigorous assessments of the
sis or major depression in most (61), but not all (62), clinical utilities of magnetic resonance imaging and single-
studies. These autoantibodies may be found in as many as photon emission computed tomography have not been
25% of unselected patients with systemic lupus erythem- done in large case series or well-controlled comparison
atosus, and thus their presence must be interpreted with trials. Furthermore, data on the diagnostic accuracy of,
caution (55). Antineuronal antibodies and antiribosomal the diagnostic and therapeutic effect of, and the change in
P protein antibodies are more likely to be seen in patients patient outcomes attributable to these tests are not avail-
with diffuse rather than focal central nervous system in- able (66, 69).
volvement. This suggests that the former may be autoan-
tibody mediated (53, 55).
The specific antigens that induce the antineuronal an- Management
tibodies are beginning to be identified. Hanson and col-
leagues (63) described a 50-kd antigen in the plasma Therapy for neuropsychiatric lupus differs according to
membrane of brain synaptic terminals (neuronal compart- the type of presentation, its severity, and the nature of the
ments vital for normal brain function) that bound anti- underlying process (for example, inflammatory or throm-
bodies present in the sera of 19 of 20 patients with botic). Unfortunately, decisions about immunosuppressive
neuropsychiatric lupus. Antiribosomal P protein antibod- therapy must currently be made in the absence of data
ies were initially found to be directed to cytoplasmic from randomized controlled studies (54). Glucocorticoids
(ribosomal) proteins. More recently, however, reactive P remain the first line of therapy for the major manifesta-
peptides have also been found on the cell surface; this tions of neuropsychiatric lupus. In patients with severe
suggests that these autoantibodies may directly affect the disease or in those who do not respond to standard
function and viability of cells that express this antigenic prednisone therapy, pulse methylprednisolone therapy
target (64). In case-control studies, anticardiolipin anti- may be helpful. Small case series (45, 70-72) have shown
bodies have been associated with specific neuropsychiatric intravenous pulses of cyclophosphamide to be useful in