Systemic Lupus Erythematosus: Emerging Concepts: Part 1: Renal, Neuropsychiatric, Cardiovascular, Pulmonary, and Hematologic Disease

Systemic 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 nephritogenic. Studies correlating the immunochemical properties of autoantibodies with the type and severity of nephritis have detected several features that may promote pathogenicity, including quantity, charge, class, isotype, idiotype, 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 progressive 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 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 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 nephritis 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 cytotoxic 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]. Nonetheless, 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 sho