R E V I E W

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 ery­thematosus 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 cyclophospha­mide 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 glu­cocorticoid therapy for the treatment of proliferative lupus nephritis, but the optimal duration and intensity of cytotoxic therapy remain undefined. Definitive stud­ies of the treatment of autoimmune thrombocytopenia and acute pulmonary disease and of the diagnosis and treatment 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 patient to patient. The diverse expression of the common lupus syndrome may result from variable abnormalities in inter­secting genetic, immunologic, hormonal, and environmen­tal pathways. Although many uncertainties about patho­genic mechanisms remain, recent advances in diagnosis and treatment have substantially improved the prognosis of patients with systemic lupus erythematosus. As mortal­ity rates decrease, issues such as comorbidity, complica­tions of therapy, and overall quality of life are receiving increased attention.

We discuss recent advances in systemic lupus erythem­atosus. 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, hor­monal 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 spec­imens from almost all patients with lupus. Approximately 75% of renal biopsy specimens reported in several series have been classified as focal proliferative, diffuse prolifer­ative, or membranous glomerulonephritis (2).

Pathogenesis

Localization of immune complexes in the kidney ap­pears 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 nephro­genic. Studies correlating the immunochemical properties of autoantibodies with the type and severity of nephritis have detected several features that may promote patho-

Ann Intern Med. 1995;122:940-950.

From the National Institutes of Health, Bethesda, Maryland. For current author addresses, see end of text.

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genicity, including quantity, charge, class, isotype, idio-type, avidity for DNA, and efficiency of complement fix­ation (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 im­mune complex formation and influences the location of these deposits within the glomerulus (4). Thus, factors that lead to the deposition of many proinflammatory im­mune complexes in the subendothelial region of the glo­merular capillary wall, adjacent to the circulation, are likely 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 to glomerular proliferation and proteinuria (6).

The subepithelial immune deposits characteristic of lu­pus membranous nephropathy probably evolve through the in situ interaction of autoantibodies with antigens, such as DNA or histones, that bind to glomerular base­ment 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 for­mation 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 com­plement abnormalities have correlated with the degree of renal histologic activity in several studies (9, 10). Persis­tent C3 or CH50 complement depression has been asso­ciated 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 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 protein excretion rate, which are frequently considered stronger indications for modifications of therapy.

Standard kidney function variables (such as serum cre­atinine level and creatinine clearance) are insensitive in­dicators 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 clear­ances or by using creatinine clearance after blocking tu­bular 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 that have been shown in animal models to augment filtration in perfused glomeruli (16).

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 usu­ally 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 as­sessment of prognosis. Hypertension has been associated with renal disease progression and death (17). The con­tribution 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 oc­curred. Kidney biopsy data provide a more direct ap­praisal of the type of renal disease and have enhanced outcome predictions based on clinical data in several (20-23), but not all (18, 24), studies. Variations in conclusions may 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 de­posits) 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 ther­apy 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 mem­branous lupus nephropathy (27).

Patients with diffuse proliferative or severe focal prolif­erative glomerulonephritis are candidates for vigorous im­munosuppressive 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 then tapering 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 glomerular capillary perfusion pressures (28) and by elevating low-density lipoprotein (LDL) cholesterol levels, leading both to 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-

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Figure 1. Treatment of severe lupus nephritis. Top. Probability of not doubling serum creatinine levels in 65 patients with severe active lupus nephritis randomly assigned to receive MP (intrave­nous methylprednisolone, 1.0 g/m2 body surface area monthly for 6 months), CY-S (intravenous cyclophosphamide, 0.5 to 1.0 g/m2

monthly for 6 months), or CY-L (intravenous cyclophosphamide, 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, P = 0.037). Bottom. Probability of no exacerbation of lupus activity on completion of monthly pulses in groups randomly assigned to receive CY-L and CY-S (Gehan test, P = 0.006). Numbers of patients that remain at risk at various times are shown along the abscissa. Reproduced with permission from Boumpas and colleagues (39).

tis and other immune-mediated disorders. Favorable short-term results have been observed (19, 30), but this therapy has been less extensively studied as a mainte­nance therapy for chronic disorders such as lupus nephri­tis (31). The effectiveness and toxicity of daily high-dose oral prednisone and pulse intravenous methylpred­nisolone therapy have not been rigorously compared in patients with lupus nephritis.

Cytotoxic Drugs Immunosuppressive drug regimens that include cyto­

toxic drugs are more efficacious than prednisone alone in controlling clinical signs of active nephritis (32, 33), in preventing renal scarring (34), and ultimately in reducing the risk for end-stage renal failure, but they have not been shown to be more effective in reducing the risk for death (35, 36). Among cytotoxic drug regimens, intermit­tent pulse cyclophosphamide therapy appears to have one of the most favorable therapeutic indexes (35-38). None­

theless, it has been recognized that intravenous pulse cyclophosphamide treatments are complicated, costly, in­convenient, 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 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 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 be­cause of the protective effects of hydration, a dilute di­uresis, and mesna (2-mercaptoethanesulfonate). Hemato­logic malignancies have been reported infrequently after intravenous cyclophosphamide therapy for lupus nephritis (41, 42). A large, multicenter study is needed to deter­mine the effect of pulse cyclophosphamide therapy on the risk for malignancy in patients with systemic lupus ery­thematosus. Sustained amenorrhea was seen in 11 of 39 women younger than 40 years of age who were treated with pulse cyclophosphamide therapy for systemic lupus erythematosus (43). The risk for sustained amenorrhea is significantly related to both the patient's age at the start of pulse therapy and the number of doses of cyclophos­phamide received. These data, coupled with observations about the risk for relapse after a short course of pulse cyclophosphamide, pose a challenging problem. Recurring inflammation may result in sclerosing lesions that increase the risk for progressive renal failure during subsequent episodes of active nephritis. A marked improvement in renal status (resolution of initial elevations in serum cre­atinine levels, low-grade proteinuria, and resolution of a nephritic urinary sediment) favor a shortened course of cytotoxic drug therapy (24). On the other hand, there is concern that discontinuing immunosuppressive therapy as soon as renal status is improved may increase the risk for relapse. Consequently, it has been recommended that pa­tients should receive quarterly pulse cyclophosphamide as maintenance therapy for approximately 1 year after achieving clinical renal remission, but this approach has never been rigorously tested.

Alternatives to this regimen of pulse cyclophosphamide therapy are currently under investigation at the National Institutes of Health and other centers (44). That more consistent 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 cyclophosphamide

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(46). Other experimental immunosuppressive regimens, including total lymphoid irradiation (47) and cyclosporine (48, 49), have been described but have not been prospec­tively 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 re­search (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 sec­ondary events, which result from disease in other organs, complications of therapy, or both (Table 1) (52-55). Pri­mary neuropsychiatric events (neuropsychiatric lupus) typ­ically 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 histopatho­logic 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 cas­es), leukoagglutination or thrombosis, and antibody-medi­ated neuronal cell injury or dysfunction. Antibodies may be produced intrathecally or may gain access to the cen­tral 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 Pa­tients 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.

Table 2. Major Neuropsychiatric Manifestations of Sys­temic 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, in­tellect 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 neuropsy­chologic testing (55, 57) and may occur independently of other manifestations of neuropsychiatric lupus or systemic disease activity (58, 59). Slow but progressive deteriora­tion 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 previ­ous 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 ex­clude acute or chronic infectious meningitis. Elevated in­trathecal 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).

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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 com­puted 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 re­solve spontaneously or with therapy or may progress to infarc­tion, 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 cyclo­phosphamide, these lesions resolved within approximately 6 months (Reproduced with permission from Boumpas and col­leagues [71]).

Autoantibodies Antineuronal antibodies are present in the serum of as

many as 75% of patients with systemic lupus erythemato­sus and neuropsychiatric lupus (53). Similarly, antiriboso-mal P protein antibodies have been found in 45% to 90% of patients with systemic lupus erythematosus and psycho­sis 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 erythem­atosus, 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 in­volvement. This suggests that the former may be autoan­tibody mediated (53, 55).

The specific antigens that induce the antineuronal an­tibodies are beginning to be identified. Hanson and col­leagues (63) described a 50-kd antigen in the plasma membrane of brain synaptic terminals (neuronal compart­ments vital for normal brain function) that bound anti­bodies present in the sera of 19 of 20 patients with neuropsychiatric lupus. Antiribosomal P protein antibod­ies 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 anti­bodies have been associated with specific neuropsychiatric

features, including cerebrovascular accidents, multi-infarc­tion dementia, seizures, intracranial arterial and venous thrombosis, chorea, and acute transverse myelitis (60, 65). With the exception of cerebrovascular accidents, the as­sociation 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 diagno­sis 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 neuro­psychiatric 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 involve­ment to have abnormalities detected by magnetic reso­nance imaging. In most cases, this imaging cannot distin­guish 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 find­ings and clinical presentation is poor. For example, inter­pretation 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 neuropsy­chiatric lupus than in patients with systemic lupus ery­thematosus and no neuropsychiatric symptoms (68). Un­fortunately, 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 avail­able (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 throm­botic). 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 manifesta­tions 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

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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-threaten­ing neuropsychiatric lupus, but only on the basis of case reports. In patients with thrombosis of intracerebral ves­sels (for example, cerebral vein thrombosis), and in the absence of generalized lupus activity or high-grade cere­brospinal fluid abnormalities, therapy should be based predominantly on anticoagulation (54). The role of im­munosuppressive therapy in these cases is not clear.

Cardiac Disease

Cardiovascular involvement has been receiving in­creased attention in patients with systemic lupus erythem­atosus. Recent prospective studies using advanced diag­nostic methods have allowed the delineation of the prevalence and significance of discrete cardiac manifesta­tions such as valvular disease, myocardial dysfunction, and pericardial disease (73-77). In other studies (78, 79), cor­onary 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 with­out valve dysfunction (regurgitation or stenosis) in addi­tion 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 trans­thoracic 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). Be­cause valvular lesions (such as Libman-Sacks endocardi­tis) may be overlooked by echocardiography and do not necessarily correlate with physical examination findings, some have suggested that antibiotic prophylaxis be con­sidered 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 wors­ened by glucocorticoids), vasculitis, or rupture of chorda tendineae (81). The relation between antiphospholipid antibodies and the development of cardiac valvular ab­normalities 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-

Table 3. Primary Respiratory System Involvement In Sys­temic 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.

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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 addi­tional pathogenetic factors may be operative in the devel­opment 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 erythem­atosus. 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 arter­ies has been well documented on autopsy studies, even in patients younger than 35 years of age.

Although the pathogenesis of accelerated atherosclero­sis is unknown, it is believed to be multifactorial. Tradi­tional 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. Circulat­ing immune complexes may promote intracellular choles­terol 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 in­terstitial pneumonia with numerous germinal centers situated adjacent to bronchial epithelium and a less prominent inflamma­tory 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 in­jury to the alveolar-capillary unit (99). Acute lupus pneu­monitis is characterized by the abrupt onset of fevers, dyspnea with hypoxemia, and patchy alveolar infiltrates on chest radiography, without evidence of an underlying in­fection. The alveolar hemorrhage syndrome, which is less common than acute lupus pneumonitis, has a similar pre­sentation, except that it is associated with an acute de­cline 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 cyclo­phosphamide is generally advocated in patients who are critically ill or unresponsive to glucocorticoids (101). Plas­mapheresis as an adjunct to immunosuppressive therapy has been used in rapidly deteriorating patients (45). Ther­apy must be initiated expeditiously because these syn­dromes can accelerate rapidly, leading to respiratory fail­ure and death. Overall mortality rates for both syndromes

are high, ranging from 50% to 90% despite treatment (93, 102). However, a recent case series of patients with sys­temic 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 favor­ably 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 ex­act 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 appro­priate 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 asso­ciated with systemic lupus erythematosus, high-resolution computed tomographic scans with a pattern that suggests chronic fibrosis may help to avoid unnecessary immuno­suppression.

Pulmonary Hypertension Increasingly recognized as a complication of systemic

lupus erythematosus, pulmonary hypertension in this con­dition closely resembles primary idiopathic pulmonary hy­pertension. The Raynaud phenomenon has been seen in as many as 75% of patients with systemic lupus erythem­atosus 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 pul­monary hypertension associated with systemic lupus erythematosus is unknown, but the condition is believed

946 15 June 1995 • Annals of Internal Medicine • Volume 122 • Number 12

to result from vascular occlusion caused by vasoconstric­tion, 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 ei­ther idiopathic or systemic lupus erythematosus. Prognosis is poor, and a steady decline in pulmonary function, de­spite treatment, is usual (109). Although it has been little studied, heart-lung transplantation may be an option in patients with systemic lupus erythematosus, advanced pul­monary 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 diagnos­tic and therapeutic problems (111). The presence of high-titer antinuclear antibodies in combination with antibod­ies 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 im­munoglobulin. Phagocytosis is more efficient when the antiplatelet antibodies belong to the IgGx and IgG2 sub­types (113). Antibodies to specific target antigens (other than the glycoprotein Ilb-IIIa complex) on platelets of patients with systemic lupus erythematosus and thrombo­cytopenia have also been described (114). Several studies have documented an association between the develop­ment of thrombocytopenia and the presence of antiphos-pholipid antibodies (115). Other case reports (116) have suggested an association between systemic lupus erythem­atosus and a syndrome similar to thrombotic thrombocy­topenic purpura. It is difficult to differentiate between thrombotic thrombocytopenic purpura and the cata­strophic occlusion syndrome in patients with antiphospho-lipid antibody. Patients with thrombocytopenia are at in­creased 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 co­agulopathy is present (117, 118). Although thrombocyto­penia rarely causes a fatal hemorrhage in patients with systemic lupus erythematosus, it may be a marker of more

aggressive and severe disease and has a substantial nega­tive effect on the prognosis of systemic lupus erythema­tosus (79).

Treatment

Randomized controlled studies of therapy for autoim­mune thrombocytopenia are not available, and treatment is based on extrapolation from studies of patients with idiopathic thrombocytopenic purpura and small case se­ries in patients with systemic lupus erythematosus. Ther­apy is aimed at attaining a complete and lasting response. If this is unsuccessful, subsequent therapy should be di­rected 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 random­ized clinical trial in children and adults with acute idio­pathic 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, intrave­nous immunoglobulin, vinca alkaloids, or intermittent pulses of methylprednisolone, dexamethasone, or cyclo­phosphamide (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 pur­pura, combination chemotherapy with cyclophosphamide and prednisone combined with either vincristine, vincris­tine 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 imple­menting 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 sys­temic 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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