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1 July 1995 | Volume 123 Issue 1 | Pages 42-53
Purpose: To review 1) advances in the pathogenesis, diagnosis, and management of dermatologic and joint disease and the antiphospholipid antibody syndrome in patients with systemic lupus erythematosus; 2) controversies related to pregnancy and hormonal therapy and to morbidity and mortality in these patients; and 3) current views on the pathogenesis of systemic lupus erythematosus. REVIEW
Systemic Lupus Erythematosus: Emerging Concepts: Part 2: Dermatologic and Joint Disease, the Antiphospholipid Antibody Syndrome, Pregnancy and Hormonal Therapy, Morbidity and Mortality, and Pathogenesis
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Data Synthesis: Despite considerable overlap, cutaneous lesions specific to lupus erythematosus may be divided into subsets with distinct clinical, histologic, and immunofluorescent features. A recent short-term, prospective, uncontrolled trial found hydroxychloroquine and retinoids to be of similar efficacy in the treatment of cutaneous lupus erythematosus. Optimal treatment for patients with lupus and the anticardiolipin antibody syndrome remains to be defined; uncontrolled, retrospective, and treatment-withdrawal studies suggest that warfarin may be more protective than aspirin. Whether pregnancy induces lupus flares has not yet been established; existing data suggest both that it does and that it does not. Oral contraceptive use and postmenopausal estrogen replacement therapy appear not to cause clinical deterioration in patients with lupus. Recent studies have documented a substantial improvement in the survival of patients with systemic lupus erythematosus; they found 5-year survival rates of 90% or more and 10-year survival rates of more than 80%. Most data suggest that systemic lupus erythematosus results from the activation of self-reactive T cells and B cells by genetic or environmental factors.
Conclusions: The optimal treatment for dermatologic disease and the antiphospholipid antibody syndrome in patients with systemic lupus erythematosus remains unknown. Although mortality has decreased substantially, the morbidity related to the disease itself and to complications of therapy is still considerable. More studies are needed to further elucidate the effects of pregnancy on this condition and the pathogenetic mechanisms responsible for the development of this disease.
Dermatologic and Joint Disease
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The term cutaneous lupus erythematosus is applied to patients with skin lesions caused by lupus erythematosus, regardless of whether the disease is confined to the skin or represents part of a more generalized systemic disease process [1]. The many morphologic variants of cutaneous lupus erythematosus may be divided into two broad categories Table 1: 1) those in which skin lesions are specific to lupus erythematosus [Figures 1, 2, and 3] and show characteristic histopathologic changes and 2) those in which skin lesions are not specific to but related to lupus erythematosus [1, 2].
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A recent study [3] compared the clinical, histologic, and immunofluorescent features of subacute cutaneous lupus erythematosus and discoid lupus erythematosus. The clinical feature most characteristic of subacute cutaneous lupus erythematosus (rather than discoid lupus erythematosus) was the presence of photosensitive, superficial, nonindurated, nonscarring lesions. Histologic examination of skin from affected areas showed a relatively sparse, superficial infiltrate in subacute cutaneous lupus erythematosus and a denser, deeper infiltrate in discoid lupus erythematosus. Epidermal IgG deposits were found only in patients with subacute cutaneous lupus erythematosus and not in patients with other forms of lupus erythematosus who showed the classic dermal-epidermal junctional staining ("lupus band") [3]. These results suggest that subacute cutaneous lupus erythematosus and chronic cutaneous lupus erythematosus probably have different pathogenetic mechanisms (antibody-mediated cytotoxicity and T cell-mediated cytotoxicity, respectively) [4].
Photosensitivity
One third to two thirds of patients with systemic lupus erythematosus have photosensitivity, which is defined as a skin rash due to an unusual reaction to sunlight. In addition to inducing rash, solar radiation may also exacerbate systemic disease activity and may have a substantial negative effect on quality of life. Solar radiation reaching the surface of the earth is composed primarily of ultraviolet A (320 to 400 nm) and ultraviolet B (290 to 320 nm) [5]. Unshielded, cool, white fluorescent lamps may also emit ultraviolet B radiation and induce disease activity in patients with photosensitive systemic lupus erythematosus [6]. Photosensitivity has been associated with the presence of anti-Ro/SS-A antibodies; as many as 70% of patients positive for anti-Ro/SS-A antibodies are reported to be photosensitive [4].
Although the mechanisms for the pathophysiologic effects of ultraviolet light are not fully understood, recent studies in patients with systemic lupus erythematosus have shown that ultraviolet light may induce the synthesis of or facilitate translocation to the plasma membrane of endogenous soluble cytoplasmic antigens (such as the Ro/SS-A, La/SS-B, Smith, and ribonucleoprotein antigens) of putative pathologic significance. Increased expression of antigens related to systemic lupus erythematosus at the plasma membrane could provide an initial antigenic stimulus for the development of specific autoantibodies and may be involved in antibody-mediated or cytotoxic cell-mediated immune response [5].
Management of Skin Disease Specific to Lupus Erythematosus
Patients who have lupus with cutaneous involvement do not seem to have more severe renal or neuropsychiatric disease than patients without cutaneous involvement. Furthermore, in populations of patients, no significant correlation exists between the rash and the exacerbation of systemic disease, but individual patients may develop rash as a first sign of flare. Thus, the existence or appearance of the rash in patients with systemic lupus erythematosus should not lead automatically to the augmentation of systemic therapy [7].
Although no controlled studies have been done, approximately 50% to 80% of patients with cutaneous lupus erythematosus will respond to antimalarial therapy. Antimalarial drugs may also have a beneficial effect on noncutaneous manifestations of systemic lupus erythematosus, such as arthralgia or arthritis and fatigue; furthermore, one study has suggested that discontinuation of antimalarial therapy may be associated with an increased risk for major flares with severe vasculitic skin ulcers, transverse myelitis, and nephritis [8]. In cutaneous lupus erythematosus resistant to antimalarial therapy, agents such as dapsone, azathioprine, thalidomide, gold, intralesional interferon, and retinoids have been used in small, uncontrolled studies [1]. In a recent randomized, double-blind, multicenter study that compared acitretin (a retinoid) with hydroxychloroquine, both drugs were of similar efficacy in improving erythema, infiltration, and scaling and hyperkeratosis [9]. Improvement was noted in approximately 50% of cases. A small sample size, asymmetrical randomization, and a short follow-up period (8 weeks) were some of the limitations of this study. Unfortunately, the long-term use of retinoids is often limited by substantial side effects (such as teratogenicity, cutaneous and mucous membrane dryness, and hyperlipidemia).
Joint Disease
Arthritis
Arthralgia or mild arthritis with morning stiffness is the most common initial manifestation of systemic lupus erythematosus; as many as 76% of patients develop true arthritis [10]. Arthritis is the first manifestation of the disease in many patients and may result in the erroneous diagnosis of rheumatoid arthritis. Patients with systemic lupus erythematosus occasionally develop nodules or joint deformities Figure 4, further accentuating the problem of differentiating this disease from rheumatoid arthritis. The coexistence of rheumatoid arthritis and systemic lupus erythematosus ("rhupus") has been seen in several patients with overlapping features of both diseases [11, 12].
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Deformities in the hand occur in as many as 10% of patients with systemic lupus erythematosus and may closely resemble those seen in patients with rheumatoid arthritis [13] (Figure 4). This pattern of nonerosive, deforming disease has been referred to as Jaccoud arthropathy because of its similarity to the arthropathy that may follow rheumatic fever. At first, the deformities due to subluxation are reversible, but, with the onset of contractures and muscle atrophy, they may become fixed [10]. Similar changes may also be seen in the feet, shoulders, or knees. A combination of periarticular fibrosis and ligamentous laxity is thought to underlie this problem; cartilage and juxta-articular bone are spared [14] (Figure 4).
Antiphospholipid Antibodies and Syndromes
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The antiphospholipid antibody syndrome consists of 1) the presence of antiphospholipid antibody identified either by high-titer enzyme-linked immunosorbent assay [ELISA] results for IgG or IgM anticardiolipin antibody or by a positive test for lupus anticoagulant and 2) the occurrence of appropriate clinical events, such as recurrent venous or arterial clotting or fetal losses. Acceptable tests for lupus anticoagulant include the dilute activated partial thromboplastin time test, the kaolin clotting time test, or the Russell viper venom time test. For clinical purposes, definition of a lupus anticoagulant requires that the results of a screening activated partial thromboplastin time test, a Russell viper venom time test, or an equivalent test be abnormal. Although some commercial laboratories now report positive "lupus anticoagulant" tests in patients with normal results on activated partial thromboplastin time tests or Russell viper venom time tests, no clinical description of the antiphospholipid antibody syndrome has yet included patients identified in these ways. Patients with positive "lupus anticoagulant" tests but normal results on activated partial thromboplastin time or Russell viper venom time tests generally have normal ELISA results for anticardiolipin antibody. The isolated "lupus anticoagulant" is thus of unknown significance.
Positive laboratory tests in clinically well persons do not justify either diagnosis of the antiphospholipid antibody syndrome or prophylactic treatment, but they do justify reexamination and monitoring of the patient. There are striking inconsistencies among commercial laboratories doing antiphospholipid antibody assays [15].
Classification
Patients with the antiphospholipid antibody syndrome who do not have systemic lupus erythematosus are considered to have the primary antiphospholipid antibody syndrome; patients with systemic lupus erythematosus who also have both antiphospholipid antibodies and relevant clinical events are considered to have the secondary antiphospholipid antibody syndrome. Because antinuclear and anti-DNA antibodies occasionally occur in patients with the primary antiphospholipid antibody syndrome, clinical criteria for both the primary antiphospholipid antibody syndrome and systemic lupus erythematosus must be present for both diagnoses to be made [16, 17]. In the secondary antiphospholipid antibody syndrome, manifestations of the primary antiphospholipid antibody syndrome adversely affect survival [18]. Some patients with systemic lupus erythematosus have transiently present (usually low-titer) antiphospholipid antibody that varies with disease activity. These patients, in contrast to those with sustained high-titer antibody, generally do not have complications of the antiphospholipid antibody syndrome [19].
Pathogenetic Mechanisms: Management
Vascular occlusion in the antiphospholipid antibody syndrome is noninflammatory and may be preceded by endothelial injury [20, 21]. It thus contrasts with vascular occlusion caused by the inflammatory vasculitis of severe systemic lupus erythematosus and with the vascular occlusion of accelerated atherosclerosis to which patients with systemic lupus erythematosus are also susceptible. In an individual patient with high-titer antiphospholipid antibody, it is often not possible to distinguish among the causes of vascular occlusion on clinical grounds alone. Livedo reticularis and chronic thrombocytopenia in the absence of both active systemic lupus erythematosus and generalized atherosclerosis support the diagnosis of the antiphospholipid antibody syndrome; the presence of extravascular evidence of active systemic lupus erythematosus suggests a diagnosis of systemic lupus erythematosus vasculitis. The distinction is worth making because the antiphospholipid antibody syndrome is treated with antiplatelet or anticoagulant drugs rather than with immunosuppressive therapy. Clinical trials in patients with the primary antiphospholipid antibody syndrome are now testing whether warfarin or aspirin is more protective against the recurrence of vascular occlusion. Uncontrolled, retrospective, and treatment-withdrawal studies favor the use of warfarin Table 2 [22].
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Growing evidence shows that antiphospholipid antibody is directed not against phospholipids but against a cofactor, ß2-glycoprotein I [23], which, on binding to phospholipid, has conformational change and probably expresses a hidden antigenic epitope [24]. Antiphospholipid antibodies may also be directed against phospholipids combined with prothrombin, protein C, protein S, or thrombomodulin. The mechanism of increased clotting in the syndrome is not yet known.
Pregnancy and Hormonal Therapy
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Systemic Lupus Erythematosus Flare
It has not been established that pregnancy induces systemic lupus erythematosus flare. Recent controlled studies have contradictorily concluded that lupus flare rates are unchanged by pregnancy [25], that they are higher in pregnant than in nonpregnant women [26], and that they are lower in pregnant women [27]. Differences among studies in referral patterns, severity of illness, histories of pregnancy, and other factors preclude consensus on whether pregnancy induces flare. Discussions of the ways in which these types of study biases influence conclusions have previously been presented [28, 29].
The diagnosis of flare in the pregnant patient with lupus can be ambiguous because, in pregnancy, common symptoms suggesting lupus flare often have causes unrelated to systemic lupus erythematosus. For instance, arthralgia, facial and palmar erythema, thrombocytopenia, proteinuria, and anemia all occur in pregnant women who do not have systemic lupus erythematosus. A low serum complement level is usually an indicator of lupus flare, but classic-pathway hypocomplementemia also occurs in pregnant patients with lupus who are clinically well. Reliable indicators of active disease in the pregnant patient with systemic lupus erythematosus include rising levels of anti-DNA antibody, alternative-pathway hypocomplementemia [30], true arthritis, true rash, mucosal ulcers, and lymphadenopathy.
Whether imputed to pregnancy or to systemic lupus erythematosus flare, clinical worsening occurs in many pregnant patients with systemic lupus erythematosus. Patients with preexisting lupus nephritis frequently have worsening of hypertension, proteinuria, and renal function during pregnancy either because of toxemia or because of renal flare [31]. Encephalopathy, hyperuricemia, abdominal pain, and hepatic failure or infarction occur in both toxemia and lupus flare. Simultaneously present extra-renal clinical and laboratory manifestations of active systemic lupus erythematosus help to distinguish between the two diagnoses in an individual patient, but even in a patient with documentable active systemic lupus erythematosus nephritis, superimposed toxemia cannot be definitively excluded. Thus, treatment of both systemic lupus erythematosus and toxemia is often appropriate. Such treatment includes high-dose prednisone therapy, antihypertensive therapy (hydralazine, methyldopa, and calcium channel blockers but not diuretics, angiotensin-converting enzyme inhibitors, and some ß-blockers), and delivery as soon as possible.
Low platelet counts occur during pregnancy in women who do not have systemic lupus erythematosus. In patients with thrombocytopenic lupus, low platelet counts may be due to pregnancy itself, to toxemia, to the antiphospholipid antibody syndrome, to systemic lupus erythematosus, or to other causes [32, 33]. In most cases, the thrombocytopenia is modest in severity (50 to 150 x 109/L). Laboratory tests such as those for platelet-associated antibodies do not distinguish among the possible causes of thrombocytopenia because such antibodies are common in patients with systemic lupus erythematosus, including those with normal platelet counts and those with nonimmunologic thrombocytopenia. Treatment may be unnecessary for mild thrombocytopenia associated with pregnancy. The platelet count of patients receiving low-dose aspirin for the antiphospholipid antibody syndrome may increase [34]. If thrombocytopenia is severe, prednisone and (if bleeding occurs or delivery is imminent) intravenous immunoglobulin are the first treatment choices.
Table 3 lists several studies of pregnancy and lupus flare. In the studies with simultaneously followed, nonpregnant controls, the flare rates for patients and controls were similar [25-27, 35-39]. Despite high overall flare rates in some series, recorded flares were usually not severe. In view of these data, and in recognition of the risk of prednisone therapy, most large clinics do not recommend prophylactic treatment for patients with lupus either during pregnancy or after delivery. Vigilance for clinical signs of flare during and after pregnancy, however, remains mandatory; treatment similar to that prescribed for nonpregnant patients (excluding teratogenic drugs) is indicated if flare occurs. Maternal complications of pregnancy other than flare and toxemia are rare. Those most frequently seen in pregnant patients with lupus, together with their clinical and serologic associations, are listed in Table 4.
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Neonatal Lupus Erythematosus
Neonatal lupus erythematosus consists of transient rash in the newborn period, permanent complete heart block, or both [40]. Fetal myocardiopathy with congestive heart failure and in utero fetal death may occur. Neonatal lupus is a rare syndrome that occurs in a minority of infants delivered only by mothers who have antibodies to the Ro/SS-A or La/SS-B antigens, or both. Approximately one third of patients with systemic lupus erythematosus have one or both of these antibodies, but maternal systemic lupus erythematosus need not be present for neonatal lupus to occur. Cutaneous neonatal lupus develops in fewer than 25% of infants born to mothers with systemic lupus erythematosus who have the associated antibodies; congenital heart block occurs in fewer than 3% [41]. In a second child, the risk for recurrence of rash is about 25% and the risk for heart block is between 8% and 16% [42, 43]. It is not possible to predict which child of a mother with anti-Ro/SS-A or anti-La/SS-B antibodies will develop the skin abnormalities of neonatal lupus, but the fine specificity of maternal autoantibodies does help to predict congenital heart block, because this occurs almost exclusively in a small proportion of infants of those mothers who have antibodies to both the Ro/SS-A 52-kd and the La/SS-B 48-kd antigens. Infants of mothers without anti-La/SS-B antibody or in whom the anti-Ro/SS-A antibody is directed only at the 60-kd and not at the 52-kd antigen appear to be at low risk [44].
The occurrence and severity of neonatal lupus are unrelated to maternal disease activity or severity. Although there is no treatment that has proved to be effective for in utero fetal myocarditis, the administration of dexamethasone to the mother (to treat the fetus) has been reported to be beneficial [45]. In a viable infant with deteriorating heart function, early delivery is indicated. Some apparently well women who have delivered a child with neonatal lupus later develop systemic lupus erythematosus [42, 43]. Approximately one third of infants with congenital heart block die before the age of 3 years, and most of the survivors require pacemakers [43].
Other Effects of Systemic Lupus Erythematosus on Fetal Outcome
Only about one half of pregnant patients with systemic lupus erythematosus deliver a full-term baby of normal weight [33, 46-48]. Causes of abnormal pregnancies are about equally divided among fetal death, prematurity, and intrauterine growth retardation. Maternal hypertension or renal disease, previous history of fetal death, or the presence of antiphospholipid antibody increase the risk. Surprisingly, lupus activity itself does not independently affect pregnancy outcome. Children born alive to mothers with systemic lupus erythematosus are generally as healthy as other newborns of similar weight and gestational age. As they grow, some may suffer mild but specific verbal processing defects that do not affect overall intelligence [49].
Antiphospholipid Antibodies in Pregnancy
In pregnant women, antiphospholipid antibody is associated with fetal death (primarily in the second trimester) [46, 47, 50, 51]. This clinical association is established for repeated positive tests for antiphospholipid antibody as defined previously. The association with fetal loss has been claimed but not established for low-titer ELISA results for antiphospholipid antibodies, IgA isotype, or antibodies to phospholipids other than cardiolipin, nor has it been established for a positive screening "lupus anticoagulant" test in patients with normal results on activated partial thromboplastin time, kaolin clotting time, or Russell viper venom time tests. Antiphospholipid antibody is only one of many predictors of fetal death; for instance, a previous fetal death is a more powerful predictor of a future fetal death than is antiphospholipid antibody [46]. Babies of affected pregnancies have intrauterine growth retardation, which is detectable by ultrasonography several weeks before fetal death occurs. Other indicators of fetal distress can be identified by antenatal fetal heart rate monitoring [52]. During pregnancy, mothers with antiphospholipid antibody may be thrombocytopenic but, for the most part, they are asymptomatic. However, they may be subject to early, severe toxemia [53]. Antiphospholipid antibody-associated renal failure also occurs, rarely, in pregnant women [54].
Treatment trials in pregnant women who have antiphospholipid antibody and who receive treatment for fetal health indications rather than for active systemic lupus erythematosus suggest that a regimen of moderate-dose heparin and low-dose aspirin improves fetal outcome [55, 56]. Other trials suggest that high-dose prednisone is unhelpful and possibly harmful [57]. Some authors advocate the use of low-dose prednisone [58], but controlled studies suggest that both high-dose [55] and low-dose [59] prednisone increase the rate of prematurity and the rate of maternal complications without improving fetal survival. The two available controlled treatment trials are described in Table 2. Because peripartum and postpartum stroke and other thrombotic events have occasionally been reported [60], therapy with low-dose aspirin, heparin, or warfarin is usually recommended for approximately 3 months after delivery for women with a history of intravascular clotting events. Some authorities recommend postpartum aspirin for all women with high-titer antiphospholipid antibody.
Hormones and Systemic Lupus Erythematosus
Oral contraceptive use, postmenopausal estrogen replacement therapy, and exogenous hormone therapy administered to support pregnancy are not known to be harmful to patients with systemic lupus erythematosus. Many patients with systemic lupus erythematosus take oral contraceptives without having clinical deterioration [61, 62]. Postmenopausal estrogen replacement therapy improves mood, general well-being, and libido without worsening systemic lupus erythematosus [63, 64]. 19-Nortestosterone does not improve the health of women with systemic lupus erythematosus, and it may worsen disease in men [65]. In animal models of systemic lupus erythematosus, feminizing manipulations usually worsen survival [66]. Because estrogens increase antiphospholipid antibody titers in mice and because oral contraceptives may promote thrombogenesis, exogenous hormones are generally withheld from women with this antibody, but no trials confirming this concern in humans have been published. Rare patients with lupus have successfully had in vitro fertilization and hormonal support for pregnancy, but this experience has not yet been reported.
Morbidity and Mortality
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Several recent studies have documented substantial improvements in the survival of patients with systemic lupus erythematosus [70-72]; 5-year survival rates of 90% or greater and 10-year survival rates of more than 80% were shown. Certainly, two of the factors contributing to improved survival have been increased awareness of systemic lupus erythematosus among physicians and the widespread use of antinuclear antibody testing. These allow for early diagnosis and the identification of many patients with mild forms of the disease and good prognosis. In addition, advances in therapeutic approaches to systemic lupus erythematosus and in general medical care—including better antibiotic and antihypertensive agents, renal dialysis and transplantation, and provisions for medical intensive care—have affected survival.
The leading causes of death in patients with lupus are infectious complications and clinical manifestations directly related to lupus itself, including acute vascular neurologic events, renal failure, and cardiovascular or pulmonary involvement. In many patients, infections develop in the setting of manifestations of active lupus under aggressive treatment; thus, it is often difficult to identify a single cause of death [73]. Coronary artery disease is becoming increasingly recognized as an important cause of death in patients with lupus [74].
Infection
Patients with lupus are prone to the development of infectious complications. Presumed immunodeficiency mechanisms associated with the disease itself appear to be primarily responsible [75], although glucocorticoids and immunosuppressive drugs may increase the risks for and the number of types of infections that develop. Prophylaxis, including antibiotic therapy for invasive dental and genitourinary procedures and immunization with influenza and pneumococcal vaccines, is generally recommended, particularly in patients with known cardiac valvular vegetations or prosthetic joints.
Although various bacterial, viral, and opportunistic infections have been associated with lupus, certain types of infections appear to occur more often than others. Herpes zoster infections have been reported at a rate of 16 episodes per 1000 patient-years; the risk for dissemination is significantly associated with immunosuppressive therapy [76]. Reports of salmonella bacteremia [77, 78], pneumococcal sepsis [79], and gram-negative polyarticular septic arthritis [80] suggest an important role for defective reticuloendothelial function in the pathogenesis of these particular infectious complications. Several recent reports have called attention to the development of Pneumocystis carinii pneumonia in patients with lupus [81-83].
Osteonecrosis
Idiopathic osteonecrosis is a relatively common debilitating complication of systemic lupus erythematosus; it is attributed either to the disease itself, to glucocorticoid therapy, or to both [84]. Whereas the role of daily oral glucocorticoid therapy in the pathogenesis of the disease is well established, it is unclear whether high-dose pulse glucocorticoid therapy is a risk factor. In a review of 22 published studies, which included 3 done in patients with systemic lupus erythematosus, oral non-bolus dose, but not bolus glucocorticoid therapy, correlated strongly with osteonecrosis [85]. In a more recent, 5-year prospective study of patients with systemic lupus erythematosus, 14% developed osteonecrosis. Both intravenous pulse glucocorticoid therapy and oral prednisolone therapy at a dose of more than 30 mg/d for at least 1 month were risk factors for osteonecrosis [86]. Small sample size (only 62 of the 212 patients enrolled originally completed the study) and the relative paucity of osteonecrotic events (n = 9) were some of the limitations of this study.
Malignancy
Although malignancy occurs infrequently in patients with systemic lupus erythematosus, a cancer-registry follow-up study of a large cohort of patients with lupus seen over a 20-year period documented increased risks for lymphoma and soft-tissue sarcomas [87]. The relative risk for non-Hodgkin lymphoma (44; 95% CI, 11.9 to 111) is approximately equal to risks in other chronic immune-mediated diseases such as the Sjogren syndrome and the Felty syndrome [88]. In addition, recent case reports of patients with lupus have called attention to the development of primary malignant lymphomas in unusual locations [89, 90].
Increased lymphoid malignancy in systemic lupus erythematosus is not an entirely unexpected finding, because spontaneous development of malignant lymphoma and macroglobulinemia has been observed in murine models of autoimmunity. It has been postulated that the pathogenesis of lymphoid malignancies in lupus results from prolonged antigenic stimulation of B lymphocytes with oligoclonal or monoclonal proliferation and eventual malignant transformation [91]. The role of increased expression of select protooncogenes, shown in the lymphocytes of patients with lupus, in the development of malignancies is uncertain [92].
Pathogenesis
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Production of autoantibodies to cellular macromolecules is the central immunologic disturbance in systemic lupus erythematosus [93]. Autoantibodies may be the actual pathogenetic agents of the disease, the secondary consequence of tissue damage, or the harmless footprints of an etiologic agent [94]. Two processes, polyclonal B-cell activation and autoantigen-driven immune stimulation, are thought to be responsible for the production of autoantibodies in systemic lupus erythematosus; evidence in lupus-prone mice suggests that polyclonal B-cell activation precedes and predicts the development of autoimmune disease [95]. In general, autoantibodies mediate tissue injury by an immune-complex-mediated inflammatory response (such as glomerulonephritis) or by autoantibody-mediated cellular dysfunction (best represented by the autoimmune cytopenias). These mechanisms are not mutually exclusive but may operate in concert. For example, pathogenic anti-DNA antibodies usually result in immune-complex-mediated renal disease, but a subset of these antibodies may also penetrate renal cells, bind to nuclei, and induce glomerular disease [96].
Anti-DNA antibodies appear to be the products of an antigen-driven, T-helper-cell-dependent immune response (see below) [97-99]. Although DNA is the target antigen, recent studies have suggested that anti-DNA antibodies may result from autoimmunization with chromatin (the complex of DNA, histones, and other proteins found in the nucleus) or nucleosome (the basic structural subunit of chromatin) rather than naked DNA [99, 100]. Furthermore, these autoantibodies may bind both DNA and components of the small nuclear ribonucleoprotein, a characteristic attributed to anti-Smith antibodies [101, 102]. These findings suggest that more than one self-antigen may drive an autoantibody response and that an autoantibody nominally directed to one self-antigen may arise from stimulation by another. Furthermore, autoantibody-producing B cells may be selected by more than one autoantigen and receive help from helper cells of different specificities, resulting in amplification of the immune response [93, 102].
Function of B and T Cells
B Cells
Activation of B cells in systemic lupus erythematosus is not randomly polyclonal (that is, directed against all possible autoantigens) but is selectively directed against a defined group of approximately 30 cellular antigens. Whereas an intrinsic B-cell defect accounting for hyperactivity has been clearly shown in animal models of systemic lupus erythematosus [103], a similar mechanism has not been convincingly shown in patients with systemic lupus erythematosus.
T Cells
Important in the development of systemic lupus erythematosus, T cells may play a major role in the activation of B cells and autoantibody production. At present, it is not clear whether systemic lupus erythematosus is the result of excessive T-cell help or defective T-cell suppression; available data support both views [104, 105]. Methylation of DNA regulates gene expression, and hypomethylation of DNA correlates with increased gene transcription. Murine (or human) antigen-specific CD4 T cells may become autoreactive after treatment with various DNA methylation inhibitors (including 5-azacytidine, procainamide, and hydralazine), and they may induce anti-DNA and antihistone antibody production and immune-complex glomerulonephritis when they are adoptively transferred into nonirradiated syngeneic recipients. These results suggest that environmental agents that inhibit DNA methylation could interact with T cells to produce a lupus-like illness, a mechanism that may have relevance to drug-induced and idiopathic systemic lupus erythematosus [106].
Genetic Factors
In lupus-prone mice, genetic factors are known to exert important influences on predisposition to systemic lupus erythematosus, but it is less clear that this occurs in humans. The concordance for systemic lupus erythematosus in monozygotic twins identified through a twin registry was relatively low (approximately 30%). Although this may be explained by nonidentity in immune repertoires and other genes caused by somatic mutations (that is, mutations induced specifically in the active lymphocyte as opposed to germ-line mutations) and other mechanisms, it has been assumed that environmental factors (microbial or nonmicrobial) must be important for the development of the disease on any particular genetic background [107].
Although the importance of genetic predisposition to systemic lupus erythematosus is well defined, the genetic basis for susceptibility to disease remains unknown [107]. Studies in lupus-prone strains of mice have provided important information on the inheritance of autoimmune traits and the roles of accelerating major histocompatibility complex, immunoglobulin, and T cell receptor genes [107, 108]. Moreover, the recent identification of polymorphic di-, tri-, or tetranucleotide repeats (microsatellites) that can be used for genotyping has made it feasible to search the entire genome for susceptibility loci in inbred mice [109]. Using linkage analysis of markers covering most of the murine genome, several disease-susceptibility loci have been identified in lupus-prone mice [110, 111]. Similar studies in families of patients with systemic lupus erythematosus may help to identify similar loci in humans.
Genes Related to Apoptosis
Apoptosis is a physiologic form of cell death (distinct from accidental cell death or necrosis) and is responsible for the deletion of unwanted cells in the process of immunologic tolerance. Several genes regulate apoptosis, including genes that antagonize (such as the Bcl-2 gene) or promote it (such as the apoptosis-1/Fas gene). The abnormal expression of apoptosis-related genes (for example, the overexpression of Bcl-2 or defects in the Fas gene) have been associated with the development of lupus-like systemic autoimmune disease in animals [112-116]. Although increased expression of Bcl-2 has been reported in the B and T cells of patients with systemic lupus erythematosus, it is not clear whether this is a primary effect or whether it merely reflects the activation of these cells [107]. Furthermore, a soluble form of the Fas protein (an apoptosis-signaling receptor molecule on the surface of lymphocytes) lacking the transmembrane domain has been found in the sera of some patients with systemic lupus erythematosus. Injection of normal mice with this soluble form of the Fas protein resulted in the inhibition of apoptosis and the appearance of autoimmune features [117]. However, in the lymphocytes of patients with systemic lupus erythematosus, normal expression and function of the apoptosis-1/Fas protein [118] and accelerated apoptosis in vitro have been reported [119]. These data should not necessarily be viewed as contradicting the hypothesis of defective apoptosis in vivo, because different environmental conditions and mechanisms for the induction of apoptosis may be operant in vitro [119].
Conclusions
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Author and Article Information
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References
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TopAuthor & Article InfoReferences |
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