Introduction

Systemic Lupus Erythematosus (SLE) is a chronic, usually life-long, potentially fatal autoimmune disease characterized by unpredictable exacerbations and remissions with protean clinical manifestations. In SLE there is a predilection for clinical involvement of the joints, skin, kidney, brain, serosa, lug, heart and gastrointestinal tract. Women and minorities are disproportionately affected and SLE is most common in women of child-bearing age although it has ben reported in both extremes of life (e.g. diagnosed in infants and in the tenth decade of life). The prevalence in the Unites States had been estimated as approximately 500,000 but a recent telephone survey commissioned by the Lupus Foundation of America suggested a prevalence of as many as 2,000,000. A recent study identified a prevalence of 500 per 100,000 (1:200) in women residing in the area surrounding Birmingham, Alabama.

The prognosis for patients with SLE has greatly improved over the last few decades with at least 80-90% of all patients surviving ten years. Thereafter life expectancy approximates that of age matched controls. This improvement reflects the general advancements in health care (i.e. dialysis, antibiotics, antihypertensives, newer immunosuppressives with more favorable efficacy to toxicity ration) but also the specialized care available for patients with SLE.

SLE is a complex disorder affecting a predominately young population and shares similarities with HIV infection as regards the propensity for multiple organ involvement, potentially life-threatening episodes, and need for sophisticated monitoring. Patients with SLE are appropriate for a Center of Excellence since medical care by experienced clinicians with access to state of the art diagnostic and therapeutic measures will result in improved outcomes and the most cost-effective utilization of resources. Expert care of patients with SLE will lead to fewer hospitalizations secondary to uncontrolled disease exacerbation, less severe renal disease with fewer patients experiencing end stage renal disease requiring chronic dialysis, fewer episodes of avascular necrosis requiring total joint replacement, and less severe osteoporosis and fractures. More judicious use of steroids and steroid sparing agents can also reduce the severity of atherosclerosis and resulting incidence of myocardial infarctions and cerebral vascular accidents which now complicate the natural history of SLE. Preventive measures such as influenza and pneumococcal vaccination, TB testing, and patient education regarding the dangers of ultraviolet light, a prudent diet, and exercise will also assure patient satisfaction and improved health status.

Clinical Discussion

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by immune dysregulation resulting in the production of antinuclear antibodies (ANA), generation of circulating immune complexes, and activation of the complement system. SLE is notable for unpredictable exacerbations and remissions and a predilection for clinical involvement of the joints, skin, kidney, brain, serosa, lung, heart, and gastrointestinal tract. The pathologic hallmark of the disease is recurrent, widespread, and diverse vascular lesions.

SLE is not a rare disorder. Although reported at both extremes of life (e.g. diagnosed in infants and in the tenth decade of life) chiefly it affects women of child bearing age. Among children, SLE occurs three times more commonly in females than in males. In the 60% of SLE patients who experience onset of their disease between puberty and the fourth decade of life the female to male ratio is 9:1. Thereafter, the female preponderance again falls to that observed in prepubescents.

The disorders is three times more common in African American blacks than American caucasians. SLE is also more common in Asians and in China may be more common than Rheumatoid Arthritis. The ethnic group at greatest risk is African Caribbean blacks. The annual incidence of SLE ranges from six to 35 new cases per 100,000 population in relatively low-risk to high-risk groups. The prevalence of SLE in the United States is an issue of some debate. Prevalence estimates of between 250,000 to 500,000 are contradicted by a recent nationwide telephone poll suggesting a prevalence of between one and two million.

The clinical features of SLE are protean and may mimic infectious mononucleosis, lymphoma, or other systemic disease. Therefore, the American College of Rheumatology developed criteria to include patients with SLE and exclude those with other disorders (Table 1). These criteria are best used to insure the appropriateness of subjects for epidemiological or research studies. Although many patients do not fulfill the rigid criteria at first encounter most will when followed over periods of time.

The etiology of SLE remains unknown. A genetic predisposition, sex hormones, and environmental trigger(s) likely result in the disordered immune response that typifies the disease.

A role for genetics is suggested by the increased percentage of two histocompatibility antigens in patients with SLE, HLA-DR2 and HLA-DR3. In addition, there is an increased frequency of the extended haplotype HLA-A1, B8, DR3. The role for heredity is further supported by the concordance for this illness among monozygotic twins. The polygenic nature, however, of this genetic predisposition as well as the contribution of environmental factors is suggested by the only moderate concordance rate which is reported to be between 25 and 60%.

The origin of autoantibody production in SLE is unclear but a role has been suggested for an antigen driven process, spontaneous B-cell hyper-responsiveness, or impaired immune regulation. Regardless of the etiology of autoantibody production, SLE is associated with the impaired clearance of circulating immune complexes secondary to decreased CR1 expression, defective Fc receptor function, or deficiencies of early complement components such as C4A.

More is known about the pathogenic cellular and molecular events which are responsible for vascular lesions in SLE than the origins of autoimmunity. Disease manifestations result from recurrent vascular injury due to immune complex deposition, leukothrombosis, or thrombosis (Table 2). Additionally, cytotoxic antibodies can mediate autoimmune hemolytic anemia and thrombocytopenia, while antibodies to specific cellular antigens can disrupt cellular function. An example of the latter, is the association between anti-neuronal antibodies and neuropsychiatric SLE.

The health status of a patient with SLE is related not only to disease activity, but to the damage that results from recurrent episodes of disease flare (i.e. deforming arthropathy, shrinking lung, end stage renal disease, organic mental syndrome, etc.), as well as the adverse effects of treatment (i.e. avascular necrosis of bone, infections, and precocious atherosclerosis, etc.).

SLE Subsets

Discoid, drug-induced, neonatal, and Ro (ANA negative) lupus are related to SLE and warrant brief description.

Discoid lupus is an illness characterized by a non-photosensitive, chronic and potentially scarring skin disease. This illness is usually unaccompanied by ANA or other autoantibodies. Perhaps 10% of patients with discoid lupus will develop the systemic illness.

Drugs such as procainamide or hydralazine can induce the production of antinuclear antibodies, especially anti-histone antibodies, and occasionally a SLE-like illness. Drug induced lupus is usually characterized by fever, hematological abnormalities such as an autoimmune hemolytic anemia or autoimmune thrombocytopenia, or serositis. Skin, renal and neurologic manifestations are uncommon.

Neonatal or congenital lupus occurs when the transplacental acquisition of autoantibodies, specifically anti-Ro (SS-A), produce int he neonate a transient photosensitive rash, confential complete heart block, thrombocytopenia or rarely hepatobiliary dysfunction.

ANA negative or Ro lupus is defined by the absence of an ANA and the present of a lupus-like illness. This disorder is manifest most often by a partially photosensitive skin rash referred to as subacute cutaneous lupus erythematosus. These patients often demonstrate anti-Ro antibodies in the serum and, given the cytoplasmic residence of the Ro antigen, these patients may be ANA negative.

Presenting Signs and Symptoms

80% of patients with SLE will present with involvement of the skin or joints. A common presenting complaint is a photosensitive rash often with alopecia. Alternatively, patients may present with arthralgia or frank arthritis. However, patients may present with fever accompanied by single organ involvement, such as inflammatory serositis, glomerulonephritis, neuropsychiatric disturbance or hematological disorder (i.e. autoimmune hemolytic anemia or thrombocytopenia). Rarely, patients present with severe, generalized acute lupus crisis with multiorgan involvement.

The course of SLE and common complications of the illness are best understood by reviewing the individual major areas of potential disease involvement.

Systemic Effects

Constitutional

90% of patients with SLE experience fatigue. Arthralgia and myalgia often accompany complaints of malaise. A less common but more serious constitutional feature of SLE is persistent fever and weight loss.

Musculoskeletal

Approximately 90% of patients with SLE have musculoskeletal symptoms. The typical clinical manifestation is arthralgia. The joints most commonly involved are the proximal interphalangeal, metacarpophalangeal, wrist, and knees. In contrast to rheumatoid arthritis, however, lupus is rarely accompanied by frank articular erosions. When arthritis occurs in SLE it usually is the consequence of periarticular inflammation with involvement of tendons. This can lead to Jaccoud's arthropathy which is notable for reducible deformities. Myalgias are another common feature of SLE. Less common is frank inflammatory myositis which occurs occasionally during the course of SLE. Steroid induced myopathy is a potential source of confusion. However, with inflammatory muscle disease, there is usually an elevation of the muscle enzymes, such as creatine phosphokinase, lactate dehydrogenase or aldolase.

Mucocutaneous

Mucosal ulcers are not an infrequent complication of lupus, occurring in 30% of patients. They most often occur on the hard or soft palate but also may be found on the nasal septum. The ulcers are usually painless and undetected by the patient but may be painful when there is a secondary infection, such as oral candidiasis. It is controversial whether the ulcers represent a simple inflammatory mucositis or a frank vasculitis of the mucous membranes.

Approximately 80% of patients with SLE have dermatological manifestations during the course of their illness. The acute cutaneous eruption is manifest as a photosensitive rash which often has a butterfly appearance by virtue of involving the bridge of the nose and malar areas of the face. A characteristic feature of this rash is sparing of the nasolabial folds. Photosensitivity is less common in patients of color but occurs in 50% of all patients with SLE. The rash of subacute cutaneous lupus is observed in anti-Ro positive patients. This eruption is intermediately photosensitive and can either have an annular, polycyclic appearance or a more papulosquamous, pityriasiform, or psoriasiform appearance. 25% of patients with SLE have discoid skin lesions. These lesions are often on the face with a predilection for the inner pinna of the ear but are not photosensitive. These lesions are characterized clinically by follicular plugging, skin atrophy, scaling, telangiectasia and skin erythema.

Alopecia occurs in 50% of patients. Typically this is manifest as reversible hair thinning during periods of disease activity. This is demonstrated by the ease with which hair can be plucked from the scalp and the development of "lupus hairs" (i.e. short strands at the scalp line). Following an acute, usually febrile, exacerbation of SLE patients may experience precipitous generalized hair loss as part of a telogen effluvium. This results from a period of arrested hair growth during the acute episode. Discoid lesions involving the scalp leads to scarring alopecia.

Unusual cutaneous manifestations of lupus include urticaria, angioedema, bullae and panniculitis known as lupus profundus.

Raynaudus phenomenon is observed in 30% of patients. Livedo reticularis occurs with increased incidence in patients with SLE. Livedo also may be a marker for patients with SLE and the secondary antiphospholipid antibody syndrome. Digital purpura is another manifestation of SLE and may occur as the consequence of vasculitis. Palpable purpura with histologic evidence of leukocytoclastic vasculitis is an occasional feature of SLE.

Serositis

Inflammatory serositis of the pleura, pericardium and peritoneum occurs in 50% of patients with SLE. This may produce pleuritis, pericarditis and medical peritonitis. These may occur in the absence of any significant effusion and represent a non-effusive serositis. Alternatively, patients can develop large pleural effusions, pericardial effusions or ascites. These effusions are typically inflammatory and exudative. Frank cardiac tamponade has been reported, albeit, on rare occasions.

Hematological

Anemia of chronic inflammation is a common feature of exacerbated SLE. Coombs positive hemolytic anemia with an acute declining hematocrit and reticulocytosis is a characteristic but not especially common occurrence in SLE, appearing in 10% of patients. Autoimmune thrombocytopenia purpura can be a presenting feature of SLE or occur at any time in the course of the illness. Thrombocytopenia as a consequence of the antiphopholipid antibody syndrome has also been described in SLE. Leukopenia with lymphopenia is also a characteristic feature of SLE. Interestingly, when this occurs in the absence of cytotoxic drug therapy of the illness, it is not a significant risk for infection.

Renal

Although pathologically the majority of patients with SLE may have glomeruplopathy clinically relevant kidney disease occurs in about 50% of patients. This is usually the consequence of the deposition of immune complexes containing anti-DNA in the kidney. Serum antibodies to anti-DNA are a marker for the development of renal disease. Hypocomplementemia is often a harbinger of active renal disease. Mesangial lupus nephropathy is generally associated with an excellent prognosis. Proliferative lupus nephropathy, especially diffuse proliferative, often has a nephritic picture with hypertension, urinary red cell casts and can be accompanied by significant deterioration in renal function. Nephrotic syndrome in the absence of hypertension, active urinary sediment, or significant hypocomplementemia suggests membranous lupus nephropathy.

Central Nervous System

Neuropsychiatric complications occur in 50% of SLE patients and include acute and chronic, as well as focal and diffuse manifestations. Cerebral vascular accidents are the consequence of either inflammatory or non-inflammatory, thrombotic vasculopathy in the central nervous system. Seizures complicate the course in 25% of patients with lupus. Diffuse cerebral dysfunction is manifest as an organic effective disorders, personality disorder, psychosis, or coma. Vascular or migraine headaches occur in 10% of lupus patients. Recurrent involvement of the central nervous system may result in an organic brain syndrome and dementia.

Secondary Antiphospholipid Antibody Syndrome

Patients with SLE have an increased incidence of the antiphopholipid antibody syndrome. This syndrome is defined by the co-occurrence of thrombotic events and the presence of autoantibodies against negatively charged phospholipid, such as a biological false-positive VDRL, lupus anticoagulant, or anti-cardiolipin antibody. This syndrome occurs most frequently in patients with high titer IgG anti-cardiolipin antibodies or lupus anticoagulant. Patients with this disorders are at risk for recurrent arterial and venous thrombosis, thrombocytopenia, and fetal wastage. The mechanisms of this prothrombotic diathesis are uncertain, but these autoantibodies, perhaps interacting with co-factors, bind to target antigens on endothelial cells, platelets or coagulation factors producing a hypercoaguable state.

Ocular

Patients with lupus may develop anterior uveitis or iridocyclitis. Frank retinal vasculitis has been described, as well as central retinal artery occlusion, central retinal vein occlusion and ischemic optic neuropathy. Xerostomia with keratoconjunctivitis sicca is seen in 10% of patients.

Lung

As mentioned, the most common involvement of the lung is inflammatory serositis producing pleuritis. However, patients with lupus can also develop transient hypoxia on the basis of pulmonary leukosequestration, inflammatory pneumonitis, interstitial pulmonary fibrosis, pulmonary hypertension, diaphragmatic dysfunction, and phrenic nerve palsy.

Cardiac

The most common cardiac manifestation is pericarditis with or without effusion. Additionally, patients with lupus can develop myocarditis. Nonbacterial verrucous endocarditis or Libman-Sacks endocarditis produces millimeter vegetation on the mitral and aortic valve. These are usually asymptomatic and an incidental pathologic finding at autopsy. Rarely, they can be a cause of cerebral or coronary artery embolization. Thrombotic valvulitis and thrombosis of cardiac chambers have been described in patients with the antiphospholipid antibody syndrome. Active SLE can be accompanied by coronary artery vasculitis and, on rare occasion, this has produced myocardial infarction.

There is an increased incidence of atherosclerotic heart disease in SLE, including in premenopausal women. This may be related to coronary artery pathology initiated by immune complex deposition, but certainly is aggravated by chronic steroid therapy which can produce hyperlipidemia and hyperglycemia. Additionally, the hyperlipidemia of the nephrotic syndrome that can accompany lupus nephritis promotes atherosclerosis. SLE patients with the secondary antiphospholipid antibody syndrome also develop myocardial infractions but on the basis of bland coronary artery thrombosis.

Gastrointestinal

Medical peritonitis with or without ascites is a manifestation of lupus serositis involving the peritoneum. Less common manifestations of lupus involving the gastrointestinal tract include mesenteric ischemia from mesenteric vasculitis and pancreatitis. The latter can be a manifestation of disease activity, or less commonly, a consequence of disease treatment as with steroids. Nonspecific inflammatory liver disease has been described in lupus. Liver function abnormalities in lupus, however, are most commonly explained by idiosyncratic reactions to aspirin, anti-inflammatory drugs, hydroxychloroquine, or azathioprine. Progression to cirrhosis as a consequence of inflammatory liver disease in SLE is rare.

Laboratory Procedures

In patients with suspected SLE, appropriate screening laboratory studies include a complete blood count, erythrocyte sedimentation rate, urinalysis, biochemical profile and antinuclear antibodies. SLE is associated with anemia of chronic inflammation, acute hemolytic anemia, leukopenia, lymphopenia, and thrombocytopenia. Elevated sedimentation rates are typical of exacerbated disease. Glomerulonephritis can be accompanied by hypoalbuminemia, hyperlipidemia, and azotemia. The urinalysis in patients with the nephrotic syndrome may demonstrate only increased protein. In the presence of proliferative nephritis patients often will have hematuria, urinary red cell casts, and white cell casts. The occasional patient with SLE inflammatory myositis may have an elevated SGOT, LDH, CPK and aldolase. In 90-95% of patients with SLE the serum ANA will be positive typically with a speckled, diffuse, or peripheral pattern.

When the ANA is negative but the diagnosis is still strongly suspected a test for anti-Ro (SS-A) and anti-La (SS-B) can be used to identify the rare patient with ANA negative, Ro lupus. Additionally, a total hemolytic complement or CH50 can be helpful. A CH50 of zero is consistent with the unusual patient who has a homozygous early complement component deficiency (e.g. C1q, C2, C4), is at risk for developing a SLE-like illness, but is ANA negative.

Once the diagnosis is more strongly suspected because of the appropriate findings on history, physical exam and screening laboratories (e.g. positive ANA) additional tests are valuable. These include anti-double stranded DNA, anti-RNP, anti-Sm, anti-Ro, anti-La, C3, and C4. 30-70% of patients with SLE will be anti-DNA positive. 30% of patients with SLE will be anti-Sm positive. The presence of anti-double stranded DNA antibodies and hypocomplementemia strongly suggests the diagnosis of lupus and identifies the patient at increase risk for glomerulonephritis.

In patients with a history of recurrent thrombosis or recurrent fetal wastage, the presence of the antiphopholipid antibody syndrome is evaluated by a VDRL, PTT, sensitive assay for lupus anticoagulant such as the dilute Russell viper venom time, and anti-cardiolipin antibodies.

Diagnostic Procedures

Plain radiographs are not routinely useful in the diagnosis or management of SLE. Since erosive arthritis is atypical, skeletal radiographs are not usually required. X-rays, however, can be used to evaluate symptomatic steroid treated patients for avascular necrosis. MRI is now recognized as the most sensitive technique to identify bone necrosis. Chest x-rays and chest CT scans are used to distinguish between infectious and inflammatory lung disease. Thoracentesis, pericardiocentesis and paracentesis may be necessary to evaluate patients with effusive serositis, especially in the presence of fever. Electrocardiograms (ECG) can demonstrate changes indicative of pericarditis. An ECG may be required to exclude myocardial infarction in SLE patients with chest pain, especially if risk factors for atherosclerosis or thrombosis are present. Echocardiograms are used to evaluate patients for pericardial effusions or valvulitis. Electroencephalograms (EEG) are useful in evaluating patients with suspected neuropsychiatric lupus. Although they are nonspecific, they are abnormal in 75% of patients with acute diffuse cerebral dysfunction. Quantitative EEG studies may provide more specific information but are not routinely available. Brain CT scans are also nonspecific and have proven less sensitive than MRI in evaluating the central nervous system. Even MRI, however, is most useful in patients with focal rather than diffuse cerebral events. Finally, PET and SPECT scans of the nervous system may prove helpful but require additional studies of their reliability.

Biopsies are infrequently required for the diagnosis of SLE. Occasionally, biopsies of the skin are useful to distinguish cutaneous manifestations of lupus from coincidental skin diseases. Lymphadenopathy occurs in 40% of patients with SLE and biopsies typically reveal reactive or immunoblastic hyperplasia. However, lymphomas occur at an increased frequency in patients with SLE and a diagnostic workup with a lymph node biopsy may be necessary to include or exclude this possibility.

Renal biopsies are often required in the management of SLE. There is some controversy as to the best timing since many rheumatologists recommend empirical therapy of initial episodes of nephritis with corticosteriods. However, for refractory, recently relapsed, or frequently relapsed renal disease a biopsy is useful, especially to identify candidates for cytotoxic therapy. This is supported by the fact that renal pathology correlates with prognosis. Pathology in the kidney can be categorized by a World Health Organization (WHO) or National Institutes of Health (NIH) classification system. In the WHO classification, mesangial and membranous lupus nephropathy have a better prognosis than proliferative forms of nephritis. However, even membranous disease with persistent nephrotic syndrome can lead to progressive renal dysfunction. Patients with focal or diffuse proliferative glomerulonephritis, especially when accompanied by chronicity changes as defined by the NIH, have the worst prognosis. In summary, renal biopsies are most useful when evaluated by light microscopy, immunofluorsence, electron microscopy, WHO classification, NIH activity and chronicity indices, and with regard to changes in the glomeruli as well as in the tubules and interstit ium.

Common Pitfalls and Errors

A common pitfall is the misinterpretation of ANA results. It is a mistake to view the ANA as diagnostic of SLE. This is especially important since 25-40% of normal, healthy adult females may be ANA positive and never develop lupus or other connective tissue disease. Additionally, the ANA may be positive transiently in response to commonplace viral infections, in the presence of chronic infections, as a consequence of therapeutic medications, secondary to chronic liver disease or positive in the presence of lymphoproliferative disorders. Titers in patients with a false-positive ANA, usually are low, tend to fluctuate (reverting at times to negative) and are unaccompanied by other cardinal signs and symptoms of SLE. The more specific autoantibodies characteristic of SLE, such as anti-DNA, anti-Sm or anti-Ro, are also absent. Therefore, patients with myalgia and arthralgia who may in fact have fibromyalgia or non-rheumatic etiologies for their complaints should not be diagnosed with SLE just because of the presence of an ANA.

The failure to recognize that SLE has a systemic yet benign form is another error. It is well established that there are patients with benign or incomplete SLE. These patients are ANA positive, have SLE, but have disease manifestations limited to mild constitutional, articular, dermatologic, and serosal features. These patients, however, are spared from the more serious renal, neurologic, hematological and visceral organ manifestations. It is not necessary to be very aggressive (i.e. oral steroids, cytotoxics, etc.), in the management of these patients. Sun-avoidance, topical steroids, nonsteroidal anti-inflammatory agents, or hydroxychloroquine are usually adequate therapy.

At the other extreme, a potential pitfall is to entertain the diagnosis of SLE, but fail to perform an adequate history, physical, and evaluation of laboratory studies to identify a patient with impending serious disease activity. Subtle signs, symptoms, or abnormalities of diagnostic laboratory studies (e.g. shortness of breath, forgetfulness, agitation, proteinuria, hematuria, hypocomplementemia, etc.) may be a harbinger of serious organ injury best treated by aggressive medical therapy. Failure to recognize the significance of these findings and, when necessary, initiate appropriate treatment will adversely affect disease outcome.