- The fluorescence patterns are not absolutely specific for the type of antibody, and because many autoantibodies may be present, combinations of patterns are frequent. The immunofluorescence test for ANAs is sensitive because it is positive in virtually every patient with SLE, but it is not specific because patients with other autoimmune diseases also frequently score positive (see Table 6-9 ). Furthermore, approximately 5% to 15% of normal individuals have low titers of these antibodies, and the incidence increases with age. Antibodies to double -stranded DNA and the so-called Smith (Sm) antigen are virtually diagnostic of SLE.

 

-  In addition to ANAs, lupus patients have a host of other autoantibodies. Some are directed against blood cells, such as red cells, platelets, and lymphocytes; others react with proteins in complex with phospholipids. In recent years there has been much interest in these so-called antiphospholipid antibodies. They are present in 40% to 50% of lupus patients. They are actually directed against epitopes of plasma proteins that are revealed when the proteins are in complex with phospholipids. Included among these proteins are prothrombin, annexin V, β₂-glycoprotein I, protein S, and protein C.^[65] Antibodies against the phospholipid–β₂-glycoprotein complex also bind to cardiolipin antigen, used in syphilis serology, and therefore lupus patients may have a false-positive test result for syphilis. Some of these antibodies interfere with in vitro clotting tests, such as partial thromboplastin time. Therefore, these antibodies are sometimes referred to as lupus anticoagulant. Despite having a circulating anticoagulant that delays clotting in vitro, these patients have complications associated with a hypercoagulable state.^[66] They have venous and arterial thromboses, which may be associated with recurrent spontaneous miscarriages and focal cerebral or ocular ischemia. This constellation of clinical features, in association with lupus, is referred to as the secondary antiphospholipid antibody syndrome. The pathogenesis of thrombosis in these patients is unknown; possible mechanisms are discussed in Chapter 4 . Some patients develop these autoantibodies and the clinical syndrome without associated SLE. They are said to have the primary antiphospholipid syndrome

 

-  The cause of SLE remains unknown, but the existence in these patients of a seemingly limitless number of antibodies against self-constituents indicates that the fundamental defect in SLE is a failure of the mechanisms that maintain self-tolerance. As is true of most autoimmune diseases, both genetic and environmental factors play a role in the pathogenesis of SLE.

 

-  SLE is a genetically complex disease with contributions from MHC and multiple non-MHC genes. Many lines of evidence support a genetic predisposition.^[68,][69]

	•	Family members of patients have an increased risk of developing SLE. As many as 20% of clinically unaffected first-degree relatives of SLE patients reveal autoantibodies and other immunoregulatory abnormalities.
	•	There is a higher rate of concordance (>20%) in monozygotic twins when compared with dizygotic twins (1% to 3%).
	•	Studies of HLA associations support the concept that MHC genes regulate production of particular autoantibodies. Specific alleles of the HLA-DQ locus have been linked to the production of anti–double-stranded DNA, anti-Sm, and antiphospholipid antibodies, although the relative risk is small.
	•	Some lupus patients (-6%) have inherited deficiencies of early complement components, such as C2, C4, or C1q. Lack of complement may impair removal of circulating immune complexes by the mononuclear phagocyte system, thus favoring tissue deposition. Knockout mice lacking C4 or certain complement receptors are also prone to develop lupus-like autoimmunity. Various mechanisms have been invoked, including failure to clear immune complexes and loss of B-cell self-tolerance. It has also been proposed that deficiency of C1q results in defective phagocytic clearance of apoptotic cells.[70] Many cells normally undergo apoptosis, and if they are not cleared their nuclear components may elicit immune responses.
	•	In animal models of SLE, several non-MHC susceptibility loci have been identified. The best-known animal model is the (NZB × NZW)F1 mouse strain. In different versions of this strain, as many as 20 loci are believed to be associated with the disease.

- .There are many indications that environmental or nongenetic factors must also be involved in the pathogenesis of SLE. Exposure to ultraviolet (UV) light exacerbates the disease in many individuals. UV irradiation may induce apoptosis in cells and may alter the DNA in such a way that it becomes immunogenic, perhaps because of enhanced recognition by TLRs.^[77] In addition, UV light may modulate the immune response, for example, by stimulating keratinocytes to produce IL-1, a cytokine known to promote inflammation. Sex hormones seem to exert an important influence on the occurrence and manifestations of SLE. During the reproductive years the frequency of SLE is 10 times greater in women than in men in the age group of 17 through 55 years, and exacerbation has been noted during normal menses and pregnancy. Drugs such as hydralazine, procainamide, and d-penicillamine can induce an SLE-like response in humans.

 

-  It is clear from this discussion that the immunological abnormalities in SLE—both documented and postulated—are as varied and complex as is the clinical presentation (discussed later). Nevertheless, an attempt can be made to synthesize the new results into a hypothetical model of the pathogenesis of SLE ( Fig. 6-27 ). UV irradiation and other environmental insults lead to the apoptosis of cells. Inadequate clearance of the nuclei of these cells results in a large burden of nuclear antigens.^[79] An underlying abnormality in B and T lymphocytes is responsible for defective tolerance, because of which self-reactive lymphocytes survive and remain functional. These lymphocytes are stimulated by self nuclear antigens, and antibodies are produced against the antigens. Complexes of the antigens and antibodies bind to Fc receptors on B cells and dendritic cells, and may be internalized. The nucleic acid components engage TLRs and stimulate B cells to produce autoantibodies and activate dendritic cells to produce interferons and other cytokines, which further enhance the immune response and cause more apoptosis. The net result is a cycle of antigen release and immune activation resulting in the production of high-affinity autoantibodies.

 

-  Regardless of the exact mechanisms by which autoantibodies are formed, they are clearly the mediators of tissue injury. Most of the visceral lesions are caused by immune complexes (type III hypersensitivity). DNA–anti-DNA complexes can be detected in the glomeruli and small blood vessels. Low levels of serum complement (secondary to consumption of complement proteins) and granular deposits of complement and immunoglobulins in the glomeruli further support the immune complex nature of the disease. Autoantibodies specific for red cells, white cells, and platelets opsonize these cells and promote their phagocytosis and lysis. There is no evidence that ANAs, which are involved in immune complex formation, can penetrate intact cells. If cell nuclei are exposed, however, the ANAs can bind to them. In tissues, nuclei of damaged cells react with ANAs, lose their chromatin pattern, and become homogeneous, to produce so-called LE bodies or hematoxylin bodies. Related to this phenomenon is the LE cell, which is readily seen when blood is agitated in vitro. The LE cell is any phagocytic leukocyte (blood neutrophil or macrophage) that has engulfed the denatured nucleus of an injured cell. The demonstration of LE cells in vitro was used in the past as a test for SLE. With new techniques for detection of ANAs, however, this test is now largely of historical interest. Sometimes, LE cells are found in pericardial or pleural effusions in patients.

 

-  To summarize, SLE is a complex disorder of multifactorial origin resulting from interactions among genetic, immunological, and environmental factors that act in concert to cause activation of helper T cells and B cells and result in the production of several species of pathogenic autoantibodies.

 

-  The morphologic changes in SLE are extremely variable, as are the clinical manifestations and course of disease. The constellation of clinical, serologic, and morphologic changes is essential for diagnosis (see Table 6-8 ). The frequency of individual organ involvement is shown in Table 6-10 . The most characteristic lesions result from immune complexes depositing in blood vessels, kidneys, connective tissue, and skin.

 

-  An acute necrotizing vasculitis involving capillaries, small arteries and arterioles may be present in any tissue.^[80] The arteritis is characterized by fibrinoid deposits in the vessel walls. In chronic stages, vessels undergo fibrous thickening with luminal narrowing.

 

-  Lupus nephritis affects up to 50% of SLE patients. The principal mechanism of injury is immune complex deposition in the glomeruli, tubular or peritubular capillary basement membranes, or larger blood vessels. Other injuries may include thrombi in glomerular capillaries, arterioles, or arteries, often associated with antiphospholipid antibodies.

 

-  All of the glomerular lesions described below are the result of deposition of immune complexes that are regularly present in the mesangium or along the entire basement membrane and sometimes throughout the glomerulus. The immune complexes consist of DNA and anti-DNA antibodies, but other antigens such as histones have also been implicated. Both in situ formation and deposition of preformed circulating immune complexes may contribute to the injury, but the reason for the wide spectrum of histopathologic lesions (and clinical manifestations) in lupus nephritis patients remains uncertain.

 

- 
A morphologic classification of lupus nephritis has proven to be clinically useful.^[81] Five patterns are recognized: minimal mesangial (class I); mesangial proliferative (class II); focal proliferative (class III); diffuse proliferative (class IV); and membranous (class V). None of these patterns is specific for lupus.

-  Mesangial lupus glomerulonephritis is seen in 10% to 25% of patients and is characterized by mesangial cell proliferation and immune complex deposition without involvement of glomerular capillaries. There is no or slight (class I) to moderate (class II) increase in both mesangial matrix and number of mesangial cells. Granular mesangial deposits of immunoglobulin and complement are always present. Classes III to V nephritis, described below, are usually superimposed on some degree of mesangial changes.

- 
Focal proliferative glomerulonephritis (class III) is seen in 20% to 35% of patients, and is defined by fewer than 50% involvement of all glomeruli. The lesions may be segmental (affecting only a portion of the glomerulus) or global (involving the entire glomerulus). Affected glomeruli may exhibit crescent formation, fibrinoid necrosis, proliferation of endothelial and mesangial cells, infiltrating leukocytes, and eosinophilic deposits or intracapillary thrombi ( Fig. 6-28 ), which often correlate with hematuria and proteinuria. Some patients may progress to diffuse proliferative glomerulonephritis. The active (or proliferative) inflammatory lesions can heal completely or lead to chronic global or segmental glomerular scarring.

-  Diffuse proliferative glomerulonephritis (class IV) is the most severe form of lupus nephritis, occurring in 35% to 60% of patients. Pathologic glomerular changes may be identical to focal (class III) lupus nephritis, including proliferation of endothelial, mesangial and, sometimes, epithelial cells ( Fig. 6-29 ), with the latter producing cellular crescents that fill Bowman's space ( Chapter 20 ). The entire glomerulus is frequently affected but segmental lesions also may occur. Both acutely injured and chronically scarred glomeruli in focal or diffuse lupus nephritis are qualitatively indistinguishable from one another; the distinction is based solely on the percentage of glomerular involvement (<50% for class III vs >50% for class IV). Patients with diffuse glomerulonephritis are usually symptomatic, showing hematuria as well as proteinuria. Hypertension and mild to severe renal insufficiency are also common.

- 
Membranous glomerulonephritis (class V) is characterized by diffuse thickening of the capillary walls, which is similar to idiopathic membranous glomerulonephritis, described in Chapter 20 . This lesion is seen in 10% to 15% of lupus nephritis patients, is usually accompanied by severe proteinuria or nephrotic syndrome, and may occur concurrently with focal or diffuse lupus nephritis.
Granular deposits of antibody and complement can be detected by immunofluorescence ( Fig. 6-30 ). Electron microscopy demonstrates electron-dense deposits that represent immune complexes in mesangial, intramembranous, subepithelial, or subendothelial locations. All classes show variable amounts of mesangial deposits. In membranous lupus nephritis, the deposits are predominantly subepithelial (between the basement membrane and visceral epithelial cells). Subendothelial deposits (between the endothelium and the basement membrane) are seen in the proliferative types (classes III and IV) but may be encountered rarely in class I, II, and V lupus nephritis ( Fig. 6-31 ). When prominent, subendothelial deposits create a homogeneous thickening of the capillary wall, which are seen by light microscopy as a “wire-loop” lesion ( Fig. 6-32 ). Such wire loops are often found in both focal and diffuse proliferative (class III or IV) lupus nephritis, which reflects active disease. Changes in the interstitium and tubules are frequently present in lupus nephritis patients. Rarely, tubulointerstitial lesions may be the dominant abnormality. Discrete immune complexes similar to those in glomeruli are present in the tubular or peritubular capillary basement membranes in many lupus nephritis patients.

-  Skin. Characteristic erythema affects the facial butterfly (malar) area (bridge of the nose and cheeks) in approximately 50% of patients, but a similar rash may also be seen on the extremities and trunk. Urticaria, bullae, maculopapular lesions, and ulcerations also occur. Exposure to sunlight incites or accentuates the erythema. Histologically the involved areas show vacuolar degeneration of the basal layer of the epidermis ( Fig. 6-33A ). In the dermis, there is variable edema and perivascular inflammation. Vasculitis with fibrinoid necrosis may be prominent. Immunofluorescence microscopy shows deposition of immunoglobulin and complement along the dermoepidermal junction ( Fig. 6-33B ), which may also be present in uninvolved skin. This finding is not diagnostic of SLE and is sometimes seen in scleroderma or dermatomyositis.

-  Joints. Joint involvement is typically a nonerosive synovitis with little deformity, which contrasts with rheumatoid arthritis.

-  Central Nervous System. The pathologic basis of central nervous system symptoms is not entirely clear, but antibodies against a synaptic membrane protein have been implicated.^[82,][83] Neuropsychiatric symptoms of SLE have often been ascribed to acute vasculitis, but in histologic studies of the nervous system in such patients significant vasculitis is rarely present. Instead, noninflammatory occlusion of small vessels by intimal proliferation is sometimes noted, which may be due to endothelial damage by antiphospholipid antibodies.

-  Pericarditis and Other Serosal Cavity Involvement. Inflammation of the serosal lining membranes may be acute, subacute, or chronic. During the acute phases, the mesothelial surfaces are sometimes covered with fibrinous exudate. Later they become thickened, opaque, and coated with a shaggy fibrous tissue that may lead to partial or total obliteration of the serosal cavity.

-  Cardiovascular system involvement may manifest as damage to any layer of the heart.^[84] Symptomatic or asymptomatic pericardial involvement is present in up to 50% of patients. Myocarditis, or mononuclear cell infiltration, is less common and may cause resting tachycardia and electrocardiographic abnormalities. Valvular abnormalities primarily of the mitral and aortic valves manifest as diffuse leaflet thickening that may be associated with dysfunction (stenosis and/or regurgitation). Valvular (or so-called Libman-Sacks) endocarditis was more common prior to the widespread use of steroids. This nonbacterial verrucous endocarditis takes the form of single or multiple 1- to 3-mm warty deposits on any heart valve, distinctively on either surface of the leaflets ( Fig. 6-34 ). By comparison, the vegetations in infective endocarditis are considerably larger, and those in rheumatic heart disease ( Chapter 12 ) are smaller and confined to the lines of closure of the valve leaflets.

-  An increasing number of patients have clinical evidence of coronary artery disease (angina, myocardial infarction) owing to coronary atherosclerosis. This complication is noted particularly in young patients with long-standing disease and especially in those who have been treated with corticosteroids. The pathogenesis of accelerated coronary atherosclerosis is unclear but is probably multifactorial. The traditional risk factors, including hypertension, obesity, and hyperlipidemia, are more common in SLE patients than in control populations. In addition, immune complexes and antiphospholipid antibodies may cause endothelial damage and promote atherosclerosis.

-  Spleen. Splenomegaly, capsular thickening, and follicular hyperplasia are common features. Central penicilliary arteries may show concentric intimal and smooth muscle cell hyperplasia, producing so-called onion-skin lesions.

-  Lungs. Pleuritis and pleural effusions are the most common pulmonary manifestations, affecting almost 50% of patients. Alveolar injury with edema and hemorrhage is less common. In some cases, there is chronic interstitial fibrosis and secondary pulmonary hypertension. None of these changes is specific for SLE.

-  Other Organs and Tissues. LE, or hematoxylin, bodies in the bone marrow or other organs are strongly indicative of SLE. Lymph nodes may be enlarged with hyperplastic follicles or even demonstrate necrotizing lymphadenitis.

- 
SLE is a multisystem disease that is highly variable in its clinical presentation. Typically, the patient is a young woman with some, but not necessarily all, of the following features: a butterfly rash over the face, fever, pain but no deformity in one or more peripheral joints (feet, ankles, knees, hips, fingers, wrists, elbows, shoulders), pleuritic chest pain, and photosensitivity. In many patients, however, the presentation of SLE is subtle and puzzling, taking forms such as a febrile illness of unknown origin, abnormal urinary findings, or joint disease masquerading as rheumatoid arthritis or rheumatic fever. ANAs are found in virtually 100% of patients, but it must be remembered that ANAs are not specific (see Table 6-9 ). A variety of clinical findings may point toward renal involvement, including hematuria, red cell casts, proteinuria, and in some cases the classic nephrotic syndrome ( Chapter 20 ). Laboratory evidence of some hematologic derangement is seen in virtually every case, but in some patients anemia or thrombocytopenia may be the presenting manifestation as well as the dominant clinical problem. In still others, mental aberrations, including psychosis or convulsions, or coronary artery disease may be prominent clinical problems. Patients with SLE are also prone to infections, presumably because of their underlying immune dysfunction and treatment with immunosuppressive drugs. The course of the disease is variable and unpredictable. Rare acute cases result in death within weeks to months. More often, with appropriate therapy, the disease is characterized by flare-ups and remissions spanning a period of years or even decades. During acute flare-ups, increased formation of immune complexes and the accompanying complement activation often result in hypocomplementemia. Disease exacerbations are usually treated by corticosteroids or other immunosuppressive drugs. Even without therapy, in some patients the disease may run a benign course with skin manifestations and mild hematuria for years. The outcome has improved significantly, and an approximately 90% 5-year and 80% 10-year survival can be expected. The most common causes of death are renal failure and intercurrent infections. Coronary artery disease is also becoming an important cause of death. Patients treated with steroids and immunosuppressive drugs incur the usual risks associated with such therapy.

-  As mentioned earlier, involvement of skin along with multisystem disease is fairly common in SLE. The following sections describe two syndromes in which the cutaneous involvement is the exclusive or most prominent feature.

-  Chronic discoid lupus erythematosus is a disease in which the skin manifestations may mimic SLE, but systemic manifestations are rare.^[85] It is characterized by the presence of skin plaques showing varying degrees of edema, erythema, scaliness, follicular plugging, and skin atrophy surrounded by an elevated erythematous border. The face and scalp are usually affected, but widely disseminated lesions occasionally occur. The disease is usually confined to the skin, but 5% to 10% of patients with discoid lupus erythematosus develop multisystem manifestations after many years. Conversely, some patients with SLE may have prominent discoid lesions in the skin. Approximately 35% of patients show a positive ANA test, but antibodies to double-stranded DNA are rarely present. Immunofluorescence studies of skin biopsy specimens show deposition of immunoglobulin and C3 at the dermoepidermal junction similar to that in SLE.

-  This condition also presents with predominant skin involvement and can be distinguished from chronic discoid lupus erythematosus by several criteria. The skin rash in this disease tends to be widespread, superficial, and nonscarring, although scarring lesions may occur in some patients. Most patients have mild systemic symptoms consistent with SLE. Furthermore, there is a strong association with antibodies to the SS-A antigen and with the HLA-DR3 genotype. Thus, the term subacute cutaneous lupus erythematosus seems to define a group intermediate between SLE and lupus erythematosus localized only to skin.<sup>[

-</sup>  A lupus erythematosus–like syndrome may develop in patients receiving a variety of drugs, including hydralazine, procainamide, isoniazid, and d-penicillamine, to name only a few.^[78] Many of these drugs are associated with the development of ANAs, but most patients do not have symptoms of lupus erythematosus. For example, 80% of patients receiving procainamide test positive for ANAs, but only one third of these manifest clinical symptoms, such as arthralgias, fever, and serositis. Although multiple organs are affected, renal and central nervous system involvement is distinctly uncommon. There are serologic and genetic differences from classical SLE, as well. Antibodies specific for double-stranded DNA are rare, but there is an extremely high frequency of antibodies specific for histone. Persons with the HLA-DR4 allele are at a greater risk of developing lupus erythematosus after administration of hydralazine. The disease remits after withdrawal of the offending drug.


References:
1. Kumar, Raminder et al.  Robbins and Cotran Pathologic Basis of Disease 8th Ed.  Sander Elsevier. 2010.