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REVIEW
Systemic Lupus Erythematosus: Emerging Concepts
Part 1: Renal, Neuropsychiatries, Cardiovascular, Pulmonary, andHematologic 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 inthe diagnosis and management of systemic lupus erythematosus with visceral involvement (renal, neuropsy-chiatric, cardiopulmonary, and hematologic disease).•
Data Sources and Study Selection:
Review of theEnglish-language medical literature with emphasis onarticles published in the last 5 years. More than 400articles were reviewed.• Dafa
Synthesis:
Recent debates pertaining to lupusnephritis have focused on the value of kidney biopsydata and the role of cytotoxic drug therapies. Manystudies have shown that estimates of prognosis areenhanced by consideration of clinical, demographic,and histologic features. For patients with severe lupusnephritis, an extended course of pulse cyclophosphamide therapy is more effective than a 6-month course ofpulse methylprednisolone therapy in preserving renalfunction.Adding a quarterly maintenance regimen tomonthly pulse cyclophosphamide therapy reduces therate of exacerbations. Plasmapheresis appears not toenhance the effectiveness of prednisone and daily oralcyclophosphamide. Small case series have shownpulses of cyclophosphamide to be beneficial in patientswith lupus and neuropsychiatric disease refractory toglucocorticoid therapy, acute pulmonary disease(pneumonitis or hemorrhage), and thrombocytopenia.Patients with systemic lupus erythematosus have anincreased prevalence of valvular and atheroscleroticheart disease, apparently because of factors related tothe disease itself and to drug therapy.•
Conclusions:
Cytotoxic agents are superior to
glu
cocorticoid therapy for the treatment of proliferativelupus nephritis, but the optimal duration and intensityof cytotoxic therapy remain undefined. Definitive studies of the treatment of autoimmune thrombocytopeniaand acute pulmonary disease and of the diagnosis andtreatment of neuropsychiatric disease are not available.
Oystemic lupus erythematosus is an extraordinarily complex autoimmune disease that touches on nearly all medical 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 patientto patient. The diverse expression of the common lupussyndrome may result from variable abnormalities in intersecting genetic, immunologic, hormonal, and environmental pathways. Although many uncertainties about pathogenic mechanisms remain, recent advances in diagnosisand treatment have substantially improved the prognosisof patients with systemic lupus erythematosus. As mortality rates decrease, issues such as comorbidity, complications of therapy, and overall quality of life are receivingincreased attention.We discuss recent advances in systemic lupus erythematosus. By necessity, this review is not comprehensive; wefocus on changing concepts and new information. In this,the first part, we review issues related to the diagnosisand management of systemic lupus erythematosus withvisceral involvement. In the second part, to be publishedin the 1 July issue, we examine selected topics related todermatologic and joint disease, as well as issues related tothe antiphospholipid antibody syndrome, pregnancy, hormonal therapy, and morbidity and mortality. We concludewith an overview of recent advances in the pathogenesisof the disease.
Renal Disease
The kidney is the viscus most commonly affected bysystemic lupus erythematosus. With the use of sensitivelight, electron, and immunofluorescence microscopy, atleast modest abnormalities are seen in kidney biopsy specimens from almost all patients with lupus. Approximately
75%
of renal biopsy specimens reported in several serieshave been classified as focal proliferative, diffuse proliferative, or membranous glomerulonephritis (2).PathogenesisLocalization of immune complexes in the kidney appears to be the inciting event for the development of lupus nephritis. Autoantibodies that react with DNA andother cellular components are characteristic of human andmurine systemic lupus erythematosus, but only a subset of the resulting immune complexes seems to be nephrogenic. Studies correlating the immunochemical propertiesof autoantibodies with the type and severity of nephritishave detected several features that may promote patho-
Ann
Intern
Med.
1995;122:940-950.From the National Institutes of Health, Bethesda, Maryland. Forcurrent author addresses, see end of text.
940
15 June 1995 •
Annals of
Internal Medicine
• Volume 122 • Number 12
genicity, including quantity, charge, class, isotype, idio-type,avidity for DNA, and efficiency of complement fixation (3). Furthermore, cross-reactivity of anti-DNAautoantibodies with glomerular cell surface antigens, aswell as with normal components of basement membraneand mesangial matrix, probably promotes glomerular immune complex formation and influences the location of these deposits within the glomerulus (4). Thus, factorsthat lead to the deposition of many proinflammatory immune complexes in the subendothelial region of the glomerular capillary wall, adjacent to the circulation, arelikely to induce (through release of complement components, cytokines, and other factors) cellular proliferation,an inflammatory response, necrosis, and eventually fibrosis (5). Furthermore, a subset of autoantibodies may penetrate glomerular cells, bind to nuclei, and contribute toglomerular proliferation and proteinuria (6).The subepithelial immune deposits characteristic of lupus membranous nephropathy probably evolve throughthe in situ interaction of autoantibodies with antigens,such as DNA or histones, that bind to glomerular basement membrane because of their affinity for basementmembrane components such as fibronectin, collagen,laminin, and heparan sulfate (7). Subepithelial immunecomplexes induce relatively little cellular proliferation orinflammatory response. Glomerular capillary wall injuryappears to be induced by complement activation and formation of the membrane attack complex, C5b-9, that hasbeen 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 complement abnormalities have correlated with
the
degree
of
renal histologic activity
in
several studies
(9, 10).
Persistent
C3 or
CH
50
complement depression
has
been associated with progression
of
kidney disease
in
some,
but not
all, groups
of
patients (10-12). Antinuclear
and
anti-DNAantibody levels have been less consistently related
to
features
of
active glomerulonephritis
(13).
Serologic abnormalities
may
develop many months before evidence
of
clinical renal involvement
and
should prompt close observation
to
detect changes
in
urinary sediment
and
proteinexcretion rate, which
are
frequently considered strongerindications
for
modifications
of
therapy.Standard kidney function variables (such
as
serum creatinine 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 filtrationrate
are
obtained
by
using inulin
or
iothalamate clearances
or by
using creatinine clearance after blocking
tu
bular secretion
of
creatinine
by
cimetidine (15). Nonetheless, even these measures
of
kidney function
may
fail
to
detect
the
extent
of
renal parenchymal injury because
of
intrarenal hemodynamic compensatory mechanisms thathave been shown
in
animal models
to
augment filtrationin perfused glomeruli
(16).
Renal Biopsy A
classic clinical syndrome
(for
example, rapidly progressive glomerulonephritis)
may, in
some cases, obviatethe need
for a
kidney biopsy
to
establish
the
type
of
lupusnephritis. Many patients, however, present with clinicalfeatures compatible with several
of the
classes
of
lupusnephritis
for
which different treatment strategies
are
usually recommended.
In
these patients, renal biopsy datamay clarify
an
ambiguous situation
and
help
to
justifyvarious therapeutic options.
In the
absence
of
significantproteinuria
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 associatedwith renal disease progression
and
death
(17). The
contribution
of
kidney morphologic evaluation
to
estimates
of
prognosis
has
been debated vigorously. Detailed recordsof
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 enhancedoutcome predictions based
on
clinical data
in
several
(20-
23),
but not all
(18,
24),
studies. Variations
in
conclusionsmay relate
to the
salutary effects
of
contemporary treatments
as
well
as to
differences
in
patient selection criteria,prognostic factors,
and
outcome measures studied. Several investigators have observed
the
prognostic effect
of
markedly active histologic features (such
as
cellular crescents, fibrinoid necrosis,
and
subendothelial immune
de
posits) combined with chronic, irreversible morphologicattributes (such
as
interstitial fibrosis, tubular atrophy,and glomerular sclerosis)
(22, 25, 26).
Treatment
Glucocorticoids A
mainstay
of the
treatment
of
systemic lupus erythematosus, glucocorticoids
are
often used alone
as
initial therapy
for
patients with lupus nephritis. Prednisone
at low to
intermediate doses
is
usually sufficient
for
patients withmesangial
and
mild focal proliferative glomerulonephritis.Studies
now in
progress
are
evaluating
the
effectivenessand toxicity
of
prednisone therapy given
on
alternate daysand
of
other treatment strategies
for
patients with membranous lupus nephropathy
(27).
Patients with diffuse proliferative
or
severe focal
prolif
erative glomerulonephritis
are
candidates
for
vigorous
im
munosuppressive treatments intended
to
control intrarenal 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
thentapering
the
dose
to
reduce
the
risk
for
glucocorticoid-associated toxicities.
The
systemic effects
of
glucocorticoids
are
well recognized. High-dose glucocorticoids
may
promote glomerular scarring
by
augmenting glomerularcapillary perfusion pressures
(28) and by
elevating
low-
density lipoprotein
(LDL)
cholesterol levels, leading bothto enhanced mesangial cell uptake
of
oxidized
LDL
cholesterol
and to
cellular injury
(29).
Pulse intravenous methylprednisolone
has
been used
as
an intensive initial therapy
for
patients with lupus nephri-15 June
1995 •
Annals
of
Internal Medicine
•
Volume 122
•
Number 12
941
Figure 1. Treatment of severe lupus nephritis. Top. Probability of not doubling serum creatinine levels in 65 patients with severeactive lupus nephritis randomly assigned to receive MP (intravenous methylprednisolone, 1.0 g/m
2
body surface area monthly for6 months), CY-S (intravenous cyclophosphamide, 0.5 to 1.0 g/m
2
monthly for 6 months), or CY-L (intravenous cyclophosphamide,0.5 to 1.0 g/m
2
monthly for 6 months followed by quarterlyinfusions for 24 months) (Gehan test comparing CY-L with MP,
P =
0.037). Bottom. Probability of no exacerbation of lupusactivity on completion of monthly pulses in groups randomlyassigned to receive CY-L and CY-S (Gehan test,
P =
0.006).Numbers of patients that remain at risk at various times areshown along the abscissa. Reproduced with permission fromBoumpas and colleagues (39).tis and other immune-mediated disorders. Favorableshort-term results have been observed (19, 30), but thistherapy has been less extensively studied as a maintenance therapy for chronic disorders such as lupus nephritis (31). The effectiveness and toxicity of daily high-doseoral prednisone and pulse intravenous methylprednisolone therapy have not been rigorously compared inpatients with lupus nephritis.
Cytotoxic Drugs
Immunosuppressive drug regimens that include cytotoxic drugs are more efficacious than prednisone alone incontrolling clinical signs of active nephritis (32, 33), inpreventing renal scarring (34), and ultimately in reducingthe risk for end-stage renal failure, but they have notbeen shown to be more effective in reducing the risk fordeath (35, 36). Among cytotoxic drug regimens, intermittent pulse cyclophosphamide therapy appears to have oneof the most favorable therapeutic indexes (35-38). Nonetheless, it has been recognized that intravenous pulsecyclophosphamide treatments are complicated, costly, inconvenient, uncomfortable, and potentially toxic.Given these concerns, additional studies have beendone to address several questions. First, could an initialintensive immunosuppressive regimen shorten the duration of treatment? Second, is there an advantage to sustained immunosuppressive therapy for lupus nephritis?And third, what are the long-term toxicities of intermittent pulse cyclophosphamide therapy?According to a recent study (39), exacerbations of active renal and extrarenal disease are significantly morelikely to occur in patients receiving an intensive 6-monthcourse of pulse cyclophosphamide than in those receivinga more sustained 30-month course (Figure 1). However,pulse cyclophosphamide therapy may be associated withsubstantial side effects. The risk for fatal opportunisticinfections of the pulmonary and central nervous systemsamong patients with active systemic lupus erythematosustreated with high-dose corticosteroids, cytotoxic drugs, orboth has been emphasized (40). Bladder cancer has beenseen in patients treated with daily oral cyclophosphamidebut has not been seen in our patients with lupus receivingpulse cyclophosphamide therapy (35, 39), presumably because of the protective effects of hydration, a dilute diuresis, and mesna (2-mercaptoethanesulfonate). Hematologic malignancies have been reported infrequently afterintravenous cyclophosphamide therapy for lupus nephritis
(41,
42). A large, multicenter study is needed to determine the effect of pulse cyclophosphamide therapy on therisk for malignancy in patients with systemic lupus erythematosus. Sustained amenorrhea was seen in 11 of 39women younger than 40 years of age who were treatedwith pulse cyclophosphamide therapy for systemic lupuserythematosus (43). The risk for sustained amenorrhea issignificantly related to both the patient's age at the startof pulse therapy and the number of doses of cyclophosphamide received. These data, coupled with observationsabout the risk for relapse after a short course of pulsecyclophosphamide, pose a challenging problem. Recurringinflammation may result in sclerosing lesions that increasethe risk for progressive renal failure during subsequentepisodes of active nephritis. A marked improvement inrenal status (resolution of initial elevations in serum creatinine levels, low-grade proteinuria, and resolution of anephritic urinary sediment) favor a shortened course of cytotoxic drug therapy (24). On the other hand, there isconcern that discontinuing immunosuppressive therapy assoon as renal status is improved may increase the risk forrelapse. Consequently, it has been recommended that patients should receive quarterly pulse cyclophosphamide asmaintenance therapy for approximately 1 year afterachieving clinical renal remission, but this approach hasnever been rigorously tested.Alternatives to this regimen of pulse cyclophosphamidetherapy are currently under investigation at the NationalInstitutes of Health and other centers (44). That moreconsistent and rapid responses could be achieved by combining pulse cyclophosphamide and pulse methylprednisolone therapies or by synchronizing pulse cyclophosphamide therapy and plasmapheresis has been suggested
(45).
Plasmapheresis appears not to enhance the effectiveness of prednisone and daily oral cyclophosphamide942 15 June 1995 •
Annals of
Internal Medicine
• Volume 122 • Number 12
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