Chapter 287 – SYSTEMIC LUPUS ERYTHEMATOSUS

Systemic lupus erythematosus (SLE) is a multisystemic autoimmune disease that results from immune system–mediated tissue damage. Manifestations of SLE can involve the skin, joints, kidney, central nervous system, cardiovascular system, serosal membranes, and the hematologic and immune systems. The disease is highly heterogeneous, with individual patients manifesting variable combinations of clinical features. In most patients with SLE the disease is characterized by a waxing and waning clinical course, although some demonstrate a pattern of chronic activity. The molecular triggers of the disease are not known, but the pathogenesis is understood to involve the production of autoantibodies exhibiting multiple specificities, with reactivity with nucleic acid–binding proteins being a common feature. Immune complexes, along with immune system cells and soluble mediators, generate inflammation and tissue damage. Therapeutic approaches generally involve immunosuppression.

Epidemiology

A notable feature of SLE is that it occurs much more frequently in females than in males. Like Hashimoto's thyroiditis and Sjögren's syndrome, the female-to-male ratio is approximately 8:1 to 9:1 in adults, and most cases are diagnosed between the ages of 15 and 44 years. Between puberty and menopause, the female-to-male ratio may be as high as 15:1. In children and women older than 55, the ratio is closer to 2:1. The prevalence of SLE is estimated to be approximately 124 per 100,000 in the United States, and the incidence of new cases is 1.8 to 7.6 per 100,000 per year. The prevalence, severity, and characteristics of disease differ in different ethnic groups, with SLE being three to four times more frequent in the African American than in the white population. The severity of disease is also greater in Hispanics than in whites, although data for Hispanic populations are less abundant. Asians may also have a higher prevalence of disease than whites. Recent studies of lupus in minority populations indicate that socioeconomic factors are major contributors to the increased prevalence and severity of disease in African Americans and Hispanics.

Pathobiology

Current understanding of lupus pathogenesis incorporates roles for genetic susceptibility based on a threshold model involving multiple genes; environmental triggers, including microbial infection, sunlight, and certain drugs; and altered immune system function. Recent advances in immunology have focused attention on the mechanisms that account for innate immune system activation. At least some of the genetic and environmental contributions to lupus are likely to promote innate immune system activation and subsequent autoimmunity. Others may contribute to inflammation and tissue damage.

Murine models have proved useful in identifying genes that could contribute to lupus susceptibility or define patterns of disease. Production of autoantibodies characteristic of SLE and development of nephritis and accelerated death have been demonstrated in numerous murine strains in which immune system genes have been modified. In most cases, no alterations have been noted in the homologous human genes. The ease of induction of lupus-like disease in murine models suggests that there are numerous possible pathogenic paths that might lead to the clinical manifestations of lupus. It is not known which of these molecular pathways are responsible for human SLE.

Genetics

An important role for a genetic contribution to lupus susceptibility in humans is suggested by the high concordance of disease in monozygotic twins (14 to 57%). Genes that might account for increased lupus susceptibility or severity include those encoding components of the complement pathway, including C1q, C2, and C4A ( Table 287-1 ). Impaired production of these early complement components may decrease the clearance of apoptotic cells, thereby augment the pool of available autoantigens, or decrease the solubility of immune complexes. Polymorphic variants in the interferon regulatory factor 5 (IRF5) and Tyk2 genes, both involved in activation of the type I interferon pathway, have been associated with a diagnosis of SLE in some populations, although altered expression or function of the associated gene products has not yet been demonstrated. Association of SLE with the major histocompatibility complex (MHC) class II alleles HLA-DR2 and HLA-DR3 has been documented in many studies and is most striking in patients expressing particular autoantibody specificities. Polymorphisms in the Fc receptor genes FCGR2A and FCGR3A have been associated with SLE nephritis, possibly based on altered clearance of immune complexes. Variants of the PDCD1 and PTPN22 genes, which encode proteins that negatively regulate T-cell activation, are also associated with SLE in some populations. Genetic variants of tumor necrosis factor (TNF) and possibly other cytokine genes may alter immune effector function and inflammatory responses. The available data suggest that a common theme among the genes that have been associated with lupus is that they confer either increased activation or impaired regulation of the innate or adaptive immune responses.

TABLE 287-1   -- CANDIDATE GENES ASSOCIATED WITH SYSTEMIC LUPUS ERYTHEMATOSUS

Gene Protein
C1QA, B, and C Complement component C1q
C2 Complement component
C4A and C4B Complement component C4
CRP C-reactive protein
FCGR2A Activating Fcγ RIIA
FCGR3A Activating Fcγ RIIIA
FCGR2B Inhibitory Fcγ RIIb
IRF5 Interferon regulatory factor 5
TYK2 Tyrosine kinase 2
MBL Mannose-binding lectin
MCP-1 Monocyte chemoattractant protein 1
DRB11501 MHC class II (DR2)
DRB10301 MHC class II (DR3)
PDCD1 Programmed cell death 1
PTPN22 Protein (lymphoid) tyrosine kinase N22
TNF Tumor necrosis factor

MHC = major histocompatibility complex.

Environmental Triggers

Several classes of potential environmental triggers for lupus have been studied. Although the female preponderance of SLE implies a role for hormonal factors in the disease, recent concepts describe a possible contribution of epigenetic modification or dosage effects of the X chromosome rather than hormonal effects per se as accounting for at least some of the sex skewing. A role for microbial triggers, particularly virus infection, has been postulated for many years, consistent with the constitutional symptoms that often characterize the earliest stage of the disease. Epstein-Barr virus has garnered particular interest among investigators because the frequency of previous infection in SLE patients is significantly higher than in the general population (99 vs. 94%). Evidence of exposure to other viruses, including cytomegalovirus, is equivalent between SLE patients and healthy control subjects. Ultraviolet light exposure is a well-described trigger of lupus flares. Possible mechanisms that account for this observation include DNA damage and induction of apoptosis of skin cells, which results in concentration of nucleic acids and associated proteins in cell membrane blebs and increased availability of these self-antigens for processing by antigen-presenting cells. Recent data also support an association between current tobacco use and anti–double-stranded DNA antibodies and lupus disease activity. Certain drugs, including procainamide and hydralazine, can induce a lupus-like syndrome, but the symptoms usually abate after discontinuing use of the drug. These agents may promote demethylation of DNA, thereby increasing the availability of immunostimulatory DNA. Sulfa antibiotics have been reported to induce lupus flare in some patients. Administration of recombinant interferon-α to patients with hematologic malignancies or hepatitis C infection has been associated with induction of a lupus-like syndrome. In addition, anti-TNF agents have induced lupus autoantibodies and occasionally clinical lupus in patients with rheumatoid arthritis.

Immunologic Triggers

Genetic and environmental factors that increase the probability of development of SLE are likely to act on the immune system to induce autoimmunity and consequent tissue inflammation and damage. In addition to mechanisms that increase the availability of self-antigens, such as ultraviolet light, altered expression of gene products that mediate or regulate apoptosis, or impaired clearance of apoptotic debris, generalized activation of the immune system contributes to autoimmunity in lupus. In parallel with the events that account for effective immune responses directed at exogenous microbes, the autoimmunity that occurs in SLE patients is likely to require activation of both innate and adaptive immune responses. The innate immune response is first activated by common molecular patterns expressed on the microbe and results in augmented antigen-presenting cell capacity and successful generation of an antigen-specific adaptive immune response. The recent description of the Toll-like receptor (TLR) family of pattern recognition receptors has provided new understanding of the mechanisms through which the innate immune system is activated by exogenous and endogenous stimuli and has led to new understanding of the important role that adjuvant-like factors that stimulate the innate immune response play in inducing a successful adaptive immune response.

Type I Interferon

Recent comprehensive studies of gene expression in peripheral blood mononuclear cells of SLE patients via microarray technology have demonstrated that activation of genes regulated by type I interferon is a common feature of patients with active disease and may represent innate immune system activation. Interferon-α is gaining attention as a soluble mediator that may be responsible for many of the immunologic alterations that have been observed in SLE and is identified as a potential therapeutic target. Immune complexes containing DNA or RNA are postulated to contribute to the production of type I interferon in SLE. Demethylated CpG-rich DNA or RNA associated with nucleic acid–binding proteins can activate plasmacytoid dendritic cells and other immune system cells through TLRs and thereby result in the production of type I interferon (interferon-α or -β) and other proinflammatory cytokines ( Fig. 287-1 ). Numerous effects of type I interferon on immune system function are consistent with the altered immune responses observed in SLE patients, including maturation of dendritic cells, increased immunoglobulin class switching to mature immunoglobulin isotypes (IgG and IgA), and induction of soluble mediators that increase B-cell differentiation and inflammatory responses, such as B-lymphocyte stimulator (BLyS) and interferon-γ. Induction of an immunostimulatory microenvironment by interferon-α may support the development of a humoral immune response directed at self-antigens, particularly intracellular particles that contain nucleic acids and nucleic acid–binding proteins. It is not known why some individuals initiate immune system activation directed at self-antigens and others do not.

Model for induction of innate immune system activation in systemic lupus erythematosus.

FIGURE 287-1  Model for induction of innate immune system activation in systemic lupus erythematosus. Both exogenous and endogenous stimuli can induce Toll-like receptor (TLR) activation and thereby result in new gene transcription. Among potential endogenous ligands are immune complexes containing DNA or RNA or matrix-derived components. TLR ligands trigger the activation of intracellular adaptors, including TIR domain–containing adapter–inducing interferon-β (Trif), Trif-related adaptor molecule (TRAM), TIR domain–containing adapter protein (TIRAP), or myeloid differentiation primary response protein 88 (MyD88), and induce transcription of type I interferons or inflammatory cytokines. Type I interferons mediate diverse effects on immune system cells, including maturation of dendritic cells, increased immunoglobulin (Ig) class switching, and induction of cytokines that promote autoimmunity and inflammation, including B-lymphocyte stimulator (BLyS), interleukin-10 (IL-10), interferon-γ, and chemokines. LPS = lipopolysaccharide.

Autoantibodies

The most characteristic lupus autoantibodies target intracellular particles containing both nucleic acid and nucleic acid–binding proteins. Understanding the significance of induction of these particular autoantibody specificities may provide clues to the etiology of SLE. A recent analysis of the spectrum of autoantibodies present in the sera of individuals in whom SLE is later diagnosed has suggested that autoantibodies reactive with certain RNA-binding proteins, including the Ro protein, occur early in the preclinical stage of the disease, along with a positive antinuclear antibody (ANA) test. These are followed by anti-DNA antibodies and, finally, by the development of antibodies specific for the spliceosomal proteins Smith (Sm) and ribonucleoprotein (RNP) at approximately the time of diagnosis ( Fig. 287-2 ). These observations suggest that individuals who demonstrate progression from a narrow focus of humoral immunity on proteins associated with RNA to antibodies that bind DNA and other specificities are those in whom sufficient autoimmunity develops to manifest clinical symptoms. Approximately a third of SLE patients have autoantibodies reactive with phospholipids or the proteins associated with them, particularly β2-glycoprotein I (β2GPI). These autoantibody specificities can also be present independently of SLE in primary antiphospholipid antibody syndrome.

Proportion of patients with positive antibody tests relative to the time of diagnosis or appearance of the first clinical manifestation of systemic lupus erythematosus

FIGURE 287-2  Proportion of patients with positive antibody tests relative to the time of diagnosis or appearance of the first clinical manifestation of systemic lupus erythematosus (SLE). For each autoantibody, the proportion of patients testing positive relative to the time of diagnosis or to the time of appearance of the first clinical criterion was assessed. In analyses of the time from antibody development to the diagnosis of SLE, antinuclear antibodies (ANAs) appeared significantly earlier than anti-Sm antibodies (Z = 3.22, P < .001) and antinuclear ribonucleoprotein (anti-nRNP) antibodies (Z = 4.18, P < .001), but not significantly earlier than anti-Ro, anti-La, antiphospholipid (APL), or anti–double-stranded DNA antibodies (anti-dsDNA).  (From Arbuckle MR, McClain MT, Rubertone MV, et al: Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med 2003;349:16.)

Immune Complexes and Complement

Tissue and organ damage in SLE is mediated by the deposition or in situ formation of immune complexes and subsequent complement activation and inflammation. The complement system, composed of more than 30 proteins that act in concert to protect the host against invading organisms, initiates inflammation and tissue injury. Complement activation promotes chemotaxis of inflammatory cells and generates proteolytic fragments that enhance phagocytosis by neutrophils and monocytes. The classical pathway is activated when antibodies bind to antigen and generate potent effectors. Alternative pathway activation mechanisms differ in that they are initiated by the binding of spontaneously activated complement components to the surfaces of pathogens or self-tissues. C3a, an anaphylatoxin that binds to receptors on leukocytes and other cells, causes activation and release of inflammatory mediators. C5a is a potent soluble inflammatory, anaphylatoxic, and chemotactic molecule that promotes recruitment and activation of neutrophils and monocytes and mediates endothelial cell activation through its receptor. The release of reactive oxygen and nitrogen intermediates is an additional mechanism that contributes to tissue damage.

Tissues targeted by immune system activity in lupus include the skin, where immune complexes and complement are deposited in a linear pattern (as demonstrated in the lupus band test, in which deposited antibodies are identified by a fluorescent tag), the glomeruli, and heart valves. Recent data also suggest that antibodies reactive with hippocampal neurons in the brain can mediate excitotoxic death. Immune and inflammatory mechanisms responsible for the vasculopathy of lupus are multifactorial and not clearly defined. Microvascular damage is observed in splenic arteries and is characterized by the typical “onionskin” pattern of concentric connective tissue deposition. In addition to vascular damage mediated by inflammation, thrombosis, including microthrombi, contributes to ischemia and cell necrosis in the brain and other organs.

Clinical Manifestations

Symptoms and Signs Constitutional Symptoms

SLE is a disease that involves virtually all components of the immune system and can be accompanied by constitutional symptoms similar to those seen in the setting of microbial infection. Fatigue, headaches, weight loss, and fevers are common, along with generalized arthralgias, myalgias, and lymphadenopathy. The level of activity of lupus typically follows a pattern of flares and remissions, although some patients sustain active disease for prolonged periods. Careful monitoring for the development of major organ system disease is important to ensure timely adjustments in medical therapy.

Cutaneous and Mucous Membranes

The skin and mucous membranes are affected in most lupus patients ( Table 287-2 ). The erythematous facial rash with a butterfly distribution across the malar and nasal prominences and sparing of the nasolabial folds is the classic rash of SLE and is seen in 30 to 60% of patients ( Fig. 287-3 ). The butterfly rash is often triggered by sun exposure, but photosensitivity can also be demonstrated diffusely in other areas of the body.

TABLE 287-2   -- CLINICAL MANIFESTATIONS OF SYSTEMIC LUPUS ERYTHEMATOSUS

Manifestation Approximate Frequency (%)
Cutaneous 88
Arthritis/arthralgias 76
Neuropsychiatric 66
Pleurisy/pericarditis 63
Anemia 57
Raynaud's phenomenon 44
Vasculitis 43
Atherosclerosis 37
Nephritis 31
Thrombocytopenia 30
Sensorimotor neuropathy 28
Cardiac valvar disease 18
Pulmonary alveolar hemorrhage 12
Pancreatitis 10
Myositis 5
Myocarditis 5
Malar rash in a patient with systemic lupus erythematosus.

FIGURE 287-3  Malar rash in a patient with systemic lupus erythematosus. Note that the rash does not cross the nasolabial fold.  (From Gladman DD, Urowitz MB: Systematic lupus erythematosus: Clinical features. In Klippel JH, Dieppe PA [eds]: Rheumatology, 2nd ed. London, Mosby, 1998.)

The discoid skin lesions are erythematous plaques with central scarring and may be covered with scale. These lesions are often seen in about 25% of patients, involve the scalp or the face and ears, and may be associated with alopecia. Discoid lesions can be present in the absence of systemic manifestations of SLE. In addition to the scarring alopecia of discoid lupus, more transient alopecia may be a clinical sign of increased disease activity and is associated with apoptosis of cells in the hair follicle.

Inflammation of the deep dermis and subcutaneous fat can result in lupus panniculitis, with firm painful nodules that sometimes adhere to the epidermis causing irregularities in the superficial skin. Subacute cutaneous lupus erythematosus is seen in sun-exposed areas and can involve erythematous plaques or psoriasiform lesions. It is associated with autoantibodies to the Ro (SSA) RNA–binding protein. Mucosal ulcerations, especially of the buccal mucosa and upper palate, result from mucositis and are typical of SLE. Manifestations of vasculopathy are also common in SLE, including arteriolar spasm or infarcts in the nail folds, a diffuse lacey pattern over the skin described as livedo reticularis, and petechial/purpuric or urticarial lesions on the extremities. Vasculopathy in SLE is often associated with the presence of antiphospholipid antibodies.

Musculoskeletal System

Arthralgias and nonerosive arthritis are among the most common clinical features of SLE and are experienced by more than 85% of patients. The proximal interphalangeal and metacarpophalangeal joints of the hand are most commonly symptomatic, along with the knees and wrists. In some patients (about 10%), deformities resulting from damage to periarticular tissue can occur, a condition termed Jaccoud's arthropathy. The heavy use of corticosteroids in many lupus patients can be accompanied by the development of osteoporosis, including osteoporotic fractures, or osteonecrosis, most commonly of the hips, although the underlying vasculopathy can also contribute to joint damage.

Inflammation of the muscles with elevated creatine phosphokinase can occur rarely in SLE, and myopathy may be observed as a consequence of corticosteroid therapy. Fibromyalgia, characterized by painful trigger points at characteristic locations, commonly accompanies SLE and can contribute to fatigue and depression.

Renal System

Kidney involvement in SLE is common, with 74% of patients being affected at some time in the course of disease, and is a poor prognostic indicator. Renal pathology is generally attributed to the deposition of circulating immune complexes or in situ formation of these complexes in glomeruli and results in the activation of complement and subsequent recruitment of inflammatory cells. In addition to glomerular inflammation, necrosis, and scarring, renal pathology is characterized by vascular lesions, including thrombotic microangiopathy and extraglomerular vasculitis, and tubulointerstitial disease, including tubular atrophy and interstitial fibrosis. Hypertension may be a consequence of significant renal involvement.

Most cases of lupus nephritis present a complex immunopathologic picture, but in general, the pattern of renal disease reflects the site of deposition of immunoglobulins and the quality of the effector mechanisms that they induce. Mesangial deposition of immunoglobulin induces mesangial cell proliferation and is associated with microscopic hematuria and mild proteinuria ( Fig. 287-4 ). Subendothelial deposition of immune complexes results in proliferative and exudative inflammation, together with hematuria, mild to moderate proteinuria, and a reduced glomerular filtration rate. Subepithelial deposition of immune complexes adjacent to podocytes and along the glomerular basement membrane can result in membranous nephritis with nephrotic-range proteinuria. In addition, antiphospholipid antibodies may support the development of thrombotic or inflammatory vascular renal lesions within or external to glomeruli.

Histopathology of lupus nephritis

FIGURE 287-4  Histopathology of lupus nephritis. A, Lupus nephritis class II. A light micrograph of a glomerulus shows mild mesangial hypercellularity (periodic acid–Schiff). B, Lupus nephritis class III (A). Light micrograph showing a glomerulus with segmental endocapillary hypercellularity, mesangial hypercellularity, capillary wall thickening, and early segmental capillary necrosis (methenamine silver). C, Lupus nephritis class IV-G (A/C). A glomerulus manifests global endocapillary proliferation, leukocyte influx and apoptotic bodies, double contours, crescent formation with tubular transformation, early sclerosis, and disruption of Bowman's capsule (periodic acid–Schiff). D, Thrombotic microangiopathy in a patient with systemic lupus erythematosus and circulating anticoagulant. A glomerulus shows severe capillary and arteriolar thrombosis, endothelial cell swelling and necrosis, neutrophil influx, and stasis of erythrocytes. No signs of immune deposits were found (methenamine silver).  (From Wenning JJ, D'Agati VD, Schwartz MM, et al: The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol 2004;15:241.)

Evaluation of renal disease in SLE includes urinalysis with microscopic analysis of urine sediment, serum blood urea nitrogen and creatinine, and 24-hour urine collection for protein and creatinine clearance. Low serum albumin would be consistent with persistent proteinuria and membranous glomerulonephritis (GN), whereas red and white blood cell casts in the urinary sediment suggest proliferative GN. Although a renal biopsy is usually performed only when the result may influence therapeutic decisions, pathologic classification of the features of renal disease can provide prognostic information.

A World Health Organization classification of lupus nephritis lesions was first published in 1975 with subsequent revisions. These classifications were reviewed and rigorously reexamined recently and resulted in publication of the International Society of Nephrology and Renal Pathology Society classification criteria for lupus GN ( Table 287-3 ). Class I and II GN involves mesangial deposition of immune complexes (class I without and class II with mesangial hypercellularity), class III describes focal GN involving <50% of total glomeruli, class IV includes diffuse GN involving 50% or more of glomeruli, class V designates membranous lupus nephritis, and class VI is characterized by advanced sclerotic lesions. Classes III and IV have subdivisions for active and sclerotic lesions, and class IV also has subdivisions for segmental and global involvement. Pathologic diagnosis should include descriptions of tubulointerstitial and vascular disease, as well as glomerular involvement.

TABLE 287-3   -- INTERNATIONAL SOCIETY OF NEPHROLOGY/RENAL PATHOLOGY SOCIETY 2003 CLASSIFICATION OF LUPUS NEPHRITIS

Class I Minimal mesangial lupus nephritis
  Normal glomeruli by light microscopy, but mesangial immune deposits by immunofluorescence
Class II Mesangial proliferative lupus nephritis
  Purely mesangial hypercellularity of any degree or mesangial matrix expansion by light microscopy, with mesangial immune deposits. May be a few isolated subepithelial or subendothelial deposits visible by immunofluorescence or electron microscopy, but not by light microscopy
Class III Focal lupus nephritis[*]
  Active or inactive focal, segmental, or global endocapillary or extracapillary glomerulonephritis involving <50% of all glomeruli, typically with focal subendothelial immune deposits, with or without mesangial alterations
Class III (A) Active lesions: focal proliferative lupus nephritis
Class III (A/C) Active and chronic lesions: focal proliferative and sclerosing lupus nephritis
Class III (C) Chronic inactive lesions with glomerular scars: focal sclerosing lupus nephritis
Class IV Diffuse lupus nephritis[†]
  Active or inactive diffuse, segmental or global endocapillary or extracapillary glomerulonephritis
  Involving ≥50% of all glomeruli, typically with diffuse subendothelial immune deposits, with or without mesangial alterations. This class is divided into diffuse segmental (IV-S) lupus nephritis when ≥50% of the involved glomeruli have segmental lesions and into diffuse global (IV-G) lupus nephritis when ≥50% of the involved glomeruli have global lesions. Segmental is defined as a glomerular lesion that involves less than half of the glomerular tuft. This class includes cases with diffuse wire loop deposits but with little or no glomerular proliferation
Class IV-S (A) Active lesions: diffuse segmental proliferative lupus nephritis
Class IV-G (A) Active lesions: diffuse global proliferative lupus nephritis
Class IV-S (A/C) Active and chronic lesions: diffuse segmental proliferative and sclerosing lupus nephritis
  Active and chronic lesions: diffuse global proliferative and sclerosing lupus nephritis
Class IV-S (C) Chronic inactive lesions with scars: diffuse segmental sclerosing lupus nephritis
Class IV-G (C) Chronic inactive lesions with scars: diffuse global sclerosing lupus nephritis
Class V Membranous lupus nephritis
  Global or segmental subepithelial immune deposits or their morphologic sequelae by light microscopy and by immunofluorescence or electron microscopy, with or without mesangial alterations
  Class V lupus nephritis may occur in combination with class III or IV, in which case both will be diagnosed
  Class V lupus nephritis shows advanced sclerosis
Class VI Advanced sclerosis lupus nephritis
  ≥90% of glomeruli globally sclerosed without residual activity

From Weening JJ, D'Agati VD, Schwartz MM, et al: The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol 2004;15:241.

* Indicate the proportion of glomeruli with active and with sclerotic lesions.
Indicate the proportion of glomeruli with fibrinoid necrosis and/or cellular crescents.

The prognosis of class I and II disease is usually good, whereas class IV, the most common form of lupus nephritis, has the worst prognosis, particularly when the serum creatinine level is elevated at the time of diagnosis. Class V nephritis occurs in 10 to 20% of patients, and the implication for long-term disease outcome depends on the degree of proteinuria, with mild proteinuria having a good prognosis and nephrotic syndrome with chronic edema having a more negative prognosis. It should be noted that renal veins can occasionally become involved with thrombosis, which then contributes to nephrotic syndrome. This complication can be evaluated by renal ultrasound.

Cardiovascular System

Pericarditis and valve nodules were among the first clinical manifestations described in SLE. It is only recently that the extent of premature atherosclerotic disease has been well documented. Pericarditis is the most common cardiac manifestation, but it is sometimes recognized only on imaging studies or at autopsy. It is a component of the generalized serositis that is often a feature of SLE and is associated with local autoantibodies and immune complexes. Pericarditis is usually manifested as substernal chest pain that is improved by bending forward and can be exacerbated by inspiration or coughing. The symptoms and effusions associated with pericarditis are quite responsive to moderate-dose (20 to 30 mg/day of prednisone) corticosteroid treatment.

Structural valve abnormalities in SLE range from the sterile nodules originally described by Libman and Sacks to nonspecific valve thickening. The nodules are immobile and usually located on the atrial side of the mitral valve and sometimes on the arterial side of the aortic valve. Right-sided lesions are very rare. These structural changes may in some cases result in valvar regurgitation. Although valve nodules are detected in the majority of patients with SLE at autopsy, clinically significant valvar heart disease is much less common (1 to 18%). The verrucous valvar lesions of Libman and Sacks are most likely inflammatory in nature and may be associated with the presence of antiphospholipid antibodies.

Premature and accelerated atherosclerosis is increasingly recognized as being prevalent in lupus patients, and preclinical atherosclerotic carotid plaque has been documented in 37% of SLE patients as opposed to 15% of age- and sex-matched controls. Traditional cardiovascular risk factors apply, but the diagnosis of SLE is itself a significant risk factor for premature atherosclerosis. Although the lupus-specific mechanisms that confer additional risk for atherosclerosis have not been defined, it is likely that chronic inflammation associated with immune system activation contributes to the accumulation of vascular damage. Mortality from atherosclerosis may be up to 10 times greater in patients with SLE than in age- and sex-matched controls.

Though not specific to SLE, Raynaud's phenomenon, characterized by episodic vasospasm and occlusion of the digital arteries in response to cold and emotional stress, is a feature in up to 60% of SLE patients and contributes to pain and sometimes necrosis of the distal ends of extremities. The character of the digits classically changes from pallor to cyanosis and then to rubor as vascular perfusion becomes impaired. In addition, small arteries, arterioles, and capillaries can be affected by vasculitis and fibrinoid necrosis with clinical manifestations that include periungual telangiectases, abdominal pain, and neuropsychiatric symptoms.

Pulmonary System

Pleuritis is the most frequent manifestation of pulmonary involvement in SLE and occurs in about 30% of patients at some point in their disease course. Pleuritis is characterized by pain on respiration and by exudative effusions. Parenchymal disease is less common but may be based on several distinct mechanisms, including pneumonitis in the absence of documented infection and sometimes involving alveolar hemorrhage (in up to 12% of patients), pulmonary embolism secondary to peripheral thrombosis, or pulmonary hypertension with increased pulmonary resistance and impaired diffusing capacity.

Neuropsychiatric Involvement

Clinical features of SLE that involve the nervous system include both neurologic and psychiatric manifestations. The central and peripheral nervous systems can be affected by the disease. The American College of Rheumatology has identified 19 neuropsychiatric syndromes that can be associated with SLE, and validation of these neuropsychiatric findings has been substantiated in several independent studies ( Table 287-4 ). The most common manifestations that are probably attributable to SLE cerebritis include cognitive dysfunction, present in 17 to 66% of SLE patients; psychosis or mood disorder, the former reported in up to 8% of patients; cerebrovascular disease in 5 to 18% of patients; and seizures, present in 6 to 51% of patients. Headaches are also common. Because none of these central nervous system manifestations are found exclusively in SLE, it can be difficult to be certain that a neuropsychiatric complaint or symptom can be attributed to SLE.

TABLE 287-4   -- NEUROPSYCHIATRIC SYNDROMES OBSERVED IN SYSTEMIC LUPUS ERYTHEMATOSUS

CENTRAL NERVOUS SYSTEM
Aseptic meningitis Cerebrovascular disease Demyelinating syndrome Headache (including migraine and benign intracranial hypertension) Movement disorder (chorea) Myelopathy Seizure disorders Acute confusional state Anxiety disorder Cognitive dysfunction Mood disorder Psychosis
PERIPHERAL NERVOUS SYSTEM
Acute inflammatory demyelinating polyradiculoneuropathy (Guillain-Barré syndrome) Autonomic disorder Mononeuropathy, single/multiplex Myasthenia gravis Neuropathy, cranial Plexopathy Polyneuropathy

From The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Arthritis Rheum 1999;42:599–608.

Evaluation of neuropsychiatric lupus depends on a careful clinical history and physical and laboratory examination and, in some cases, imaging studies and analysis of cerebrospinal fluid to rule out infection. Magnetic resonance imaging is useful for detecting intracranial abnormalities, which are seen in 19 to 70% of patients and include white matter lesions, cerebral infarction, venous sinus thrombosis, and sometimes atrophy. More sophisticated imaging techniques such as magnetic resonance angiography and magnetic resonance spectroscopy can be used to assess cerebral blood flow or neuronal metabolism.

Cranial nerve and ocular involvement, most likely based on vasculopathy and focal ischemia, can sometimes affect vision. Ocular examination of the retina can reveal cotton-wool spots as a result of retinal ischemia or necrosis. Though rare, transverse myelopathy, frequently associated with antiphospholipid antibodies, can have devastating consequences, including paraplegia. Sensorimotor neuropathies, often asymmetrical, are more common (up to 28%) and are based on damage to small nerve fibers with vasculopathy in the small arteries that supply the nerve fibers.

As is the case with lupus nephritis, the pathophysiologic mechanisms that account for the neuropsychiatric manifestations of SLE are diverse and complex. Recent data suggest that autoantibodies cross-reactive with neuronal cell surface glutamate receptors and DNA may mediate excitotoxic death of neurons. The hypothesis that these autoantibodies are associated with altered cognitive functioning is being addressed in murine models, and parallel studies in lupus patients are under way. Antibodies directed against ribosomal P protein have also been associated with neuropsychiatric lupus, and antiphospholipid antibodies can contribute to a procoagulant state, vascular thrombosis, and cerebral ischemia. Cerebral vasculopathy has been clearly demonstrated by angiographic and pathologic studies. Noninflammatory small vessel vasculopathy is the most common lesion and can be associated with microinfarcts. Inflammatory mediators, including the cytokines interleukin-6 and interferon-α, and matrix metalloproteinases may also contribute to the neuropsychiatric manifestations of SLE.

Gastrointestinal System

Though uncommon, vasculitis of the gastrointestinal tract or mesentery can result in pain and bowel necrosis. Less common than pleuritis and pericarditis, peritonitis can be manifested as peritoneal effusion and abdominal pain. Pancreatitis occurs in less than 10% of patients but may also be due to vascular pathology. Lupoid hepatitis, a syndrome that was named for the presence of positive ANAs in patients with chronic active hepatitis, is a misnomer because elevated transaminases are only rarely seen in lupus patients.

Lymphadenopathy

About a third of SLE patients demonstrate diffuse lymphadenopathy at some time during the course of their disease. The nodes are often nontender, and lymphoma is sometimes considered in the differential diagnosis. Biopsy usually reveals follicular hyperplasia, although some histopathologic findings appear similar to the histiocytic necrotizing lymphadenitis that is a feature of Kikuchi's disease, a self-limited syndrome characterized by fever and lymphadenopathy. Recent multicenter studies have determined the frequency of malignancies in patients with SLE and have found a significant increase in hematologic malignancies, particularly non-Hodgkin's lymphoma. Splenomegaly is sometimes seen in SLE and is characterized by a classic “onionskin” histology that appears as concentric circles of collagen matrix surrounding splenic arteries and arterioles.

Hematologic System

In addition to autoantibody specificities that are fairly specific for SLE (anti-DNA, anti-Sm), antibodies that target each of the cellular blood elements are also common. Anemia is present in about 50% of patients and is multifactorial. It can be associated with a positive Coombs test or microangiopathic hemolysis or reflect chronic disease (normochromic, normocytic). Leukopenia, particularly lymphopenia, is observed, with the lymphocyte count decreasing in the setting of increased disease activity. Antibodies that bind to lymphocytes and neutrophils have been described, and an increased tendency for lymphocytes to undergo spontaneous apoptosis may contribute to lymphopenia. Idiopathic thrombocytopenic purpura can be an early manifestation of SLE, and thrombocytopenia, induced by antiplatelet antibodies, can sometimes lead to a life-threatening risk for hemorrhage. Antibodies to clotting factors can also occur and contribute to impaired clot formation and hemorrhage.

Lupus Pregnancy and Neonatal Lupus

Whether pregnancy increases the likelihood of lupus exacerbation has been debated, with different data on this point presented by different investigators. However, abundant data indicate that patients with SLE have worse fetal outcomes than healthy individuals do. Gestational hypertension, fetal growth restriction, and fetal distress are increased in patients with SLE and may lead to fetal loss or premature delivery. Preeclampsia can contribute to a poor outcome in both the mother and fetus and can be difficult to distinguish from a lupus flare associated with lupus nephritis.

Neonatal lupus is a distinct entity that can occur in infants of mothers with or without a diagnosis of SLE. The syndrome is characterized by cutaneous lesions and congenital heart block in the infant and the presence of antibodies to the Ro (SSA) or La (SSB) RNA–binding proteins (or both) in the mother. Mortality in babies with a congenital heart block is 15 to 31%. Deposition of anti-Ro IgG in the fetal heart, indicative of transplacental transfer of maternal autoantibody, and dense connective tissue encompassing the conduction system have been demonstrated in autopsy specimens. Prenatal testing of lupus mothers for the presence of anti-Ro and anti-La antibodies is appropriate, and careful monitoring with fetal echocardiography starting at week 16 of pregnancy can detect conduction defects. Fluorinated corticosteroids such as dexamethasone have been effective in reversing heart block in some cases.

Antiphospholipid Antibody Syndrome

Antiphospholipid antibodies represent a distinct class of autoantibodies that are seen in about a third of SLE patients but can also be present in individuals who do not carry a diagnosis of SLE. Although these antibodies were initially thought to be specific for phospholipids exposed in cell membranes, particularly after “flipping” of the membranes of apoptotic cells, extensive data support their primary reactivity with phospholipid-binding proteins, particularly β2GPI. Whether in primary antiphospholipid syndrome or in SLE, antiphospholipid antibodies have been associated with venous and arterial thromboses. In addition to vascular thromboses, clinical manifestations of antiphospholipid syndrome include thrombotic microangiopathic glomerular disease, cardiac valve lesions, livedo reticularis, thrombocytopenia, hemolytic anemia, and central nervous system disease. Recent data indicate that these autoantibodies can contribute to fetal loss and growth restriction by binding to the placenta, activating the complement system, and inducing inflammation. Catastrophic antiphospholipid syndrome, triggered by the acute onset of multisystemic (three or more organs) thrombosis, is resistant to anticoagulation treatment and is fatal in approximately 50% of cases.

Diagnosis Classification

Criteria for the classification of patients with SLE for the purpose of clinical studies were developed by the American College of Rheumatology, with the most recent full revision published in 1982 and an update published in 1997 ( Table 287-5 ). The criteria include 11 features that encompass manifestations of skin and mucosal involvement, arthritis, serositis, renal disorder, neurologic disorder, hematologic disorder, immunologic disorder, and an abnormal titer in the ANA test, with at least four criteria required for classification as SLE. ANA has low specificity but strengthens the sensitivity of the criteria because as it is positive in virtually all lupus patients. These criteria are not intended for use as diagnostic criteria because more than 50% of patients with SLE do not meet four criteria at any point in time, although all do meet these criteria at some point during the course of the disease. The criteria are useful in reminding the clinician of the most characteristic features of SLE, but a careful history with detailed review of systems and triggering factors, as well as a family history, is essential in raising suspicion of a diagnosis of SLE. Because drugs can trigger a lupus-like syndrome, a careful drug history should be taken. At the onset of clinical symptoms, the diagnosis of SLE can be uncertain because many of the systemic manifestations of lupus can mimic other conditions, particularly viral infections or malignancy, and only some of the typical clinical symptoms may be expressed at one point in time. Important features of SLE that should be borne in mind are its multisystemic nature and characteristic serology. The differential diagnosis of SLE includes other rheumatic disorders, such as rheumatoid arthritis or vasculitis; infections, including gonococcal arthritis, parvovirus B19, and mononucleosis; inflammatory bowel disease; thrombotic thrombocytopenic purpura; drug reactions; and malignancies, particularly lymphoma.

TABLE 287-5   -- UPDATE OF THE 1982 REVISED CRITERIA FOR CLASSIFICATION OF SYSTEMIC LUPUS ERYTHEMATOSUS

Criterion[*] Definition
   1.    Malar rash
Fixed erythema, flat or raised, over the malar eminences that tends to spare the nasolabial folds
   2.    Discoid rash
Erythematous raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur in older lesions
   3.    Photosensitivity
Rash as a result of unusual reaction to sunlight, by history or physician observation
   4.    Oral ulcers
Oral or nasopharyngeal ulceration, usually painless, observed by a physician
   5.    Arthritis
Nonerosive arthritis involving 2 or more peripheral joints and characterized by tenderness, swelling, or effusion
   6.    Serositis
A. Pleuritis—convincing history of pleuritic pain or rubbing heard by a physician or evidence of pleural effusion
  or
  B. Pericarditis—documented by electrocardiography, a rub, or evidence of pericardial effusion
   7.    Renal disorder
A. Persistent proteinuria greater than 0.5 g/day or greater than 3+ if quantitation is not performed or
  B. Cellular casts—may be red cell, hemoglobin, granular, tubular, or mixed
   8.    Neurologic disorder
A. Seizures—in the absence of offending drugs or known metabolic derangements; e.g., uremia, ketoacidosis, or electrolyte imbalance or
  B. Psychosis—in the absence of offending drugs or known metabolic derangements, e.g., uremia, ketoacidosis, or electrolyte imbalance
   9.    Hematologic disorder
A. Hemolytic anemia—with reticulocytosis or
  B. Leukopenia—less than 4000/mm3 total on 2 or more occasions or
  C. Lymphopenia—less than 1500/mm3 on 2 or more occasions or
  D. Thrombocytopenia—less than 100,000/mm3 in the absence of offending drugs
   10.  Immunologic disorder
A. Deleted in 1997 update
  B. Anti-DNA: antibody to native DNA in abnormal titer or
  C. Anti-Sm: presence of antibody to Sm nuclear antigen or
  D. Positive finding of antiphospholipid antibodies based on (1) an abnormal serum level of IgG or IgM anticardiolipin antibodies, (2) a positive test for lupus anticoagulant using a standard method, or (3) a false-positive serologic test for syphilis known to be positive for at least 6 months and confirmed by Treponema pallidum immobilization or the fluorescent treponemal antibody absorption test (modified in the 1997 update)