Systemic Lupus Erythematosus: A Review
Author: Keith K. Colburn, MD, Associate Professor of Medicine, Loma Linda University, Chief of Rheumatology, Loma Linda University Medical Center and Loma Linda VA Hospital,Loma Linda, CA.
Peer Reviewer: Margaret-Mary Holyst, MD, Research Assistant Professor, Department of Internal Medicine, University of Missouri-Columbia, Columbia, MO.
Editor's Note-Systemic lupus erythematosus (SLE) is a very complicated autoimmune syndrome involving potentially all organ systems. A plethora of autoantibodies are produced in patients with SLE, including some that appear to be pathogenic for certain features of the disease, most notably anti:dsDNA antibodies. The minimum requirement for the diagnosis of SLE is to know and understand the 11 American College of Rheumatology diagnostic criteria. Treatment of patients with SLE is related to the severity of the disease and may be somewhat benign for mild disease or very risky for severe, life-threatening complications, including nephritis, pulmonary hemorrhage, and serious CNS involvement. The leading cause of death in SLE is related to complications of treatment. This article will help guide physicians through the many facets of the diagnosis and treatment of patients with SLE.
Introduction and History
Systemic lupus erythematosus (SLE) is a syndrome with many different presentations and can affect most organ systems. SLE is a prototype of autoimmune diseases in which a wide variety of autoantibodies are produced, some of which may be pathogenic, causing tissue injury. The most characteristic of these antibodies are to double-stranded (ds) or native DNA.1
Sir William Osler first described the syndrome of SLE with its systemic manifestations in 1895.2 Prior to that time, lupus was considered a destructive skin disease. Osler suggested that the pathophysiology of SLE was based on the inflammation of blood vessels, or vasculitis. Soon others described specific pathogenic lesions in multiple organs, including glomerulonephritis, heart valve vegetations, arthritis, pericarditis, and numerous other findings now associated with SLE.3 The first diagnostic test for SLE, the lupus erythematosus cell prep (LE prep), was described by Hargraves in 1948, followed by an increase in the frequency of detection of this disease.4 The discovery of the LE prep opened the door to the understanding of the immunologic basis of SLE.
In the early 1950s, with the advent of the use of corticosteroids to treat patients with SLE, a marked improvement in the prognosis of lupus was noted.5 The subsequent explosion of information using newer immunologic, molecular biologic, and genetic tools has substantially increased the understanding of SLE and improved the treatment of this disease. However, the etiology of lupus still remains a mystery.
The essentials of the diagnosis and management of patients with SLE are in the understanding and recognition of the disease manifestations. It is especially important to be familiar with the American College of Rheumatology (ACR) diagnostic criteria (Table 1) and know what, when, and how much to treat.6 The cause of death in SLE patients often has an iatrogenic basis related to the lack of early recognition and the inappropriate treatment of the actual or presumed manifestations of this disease.
Epidemiology
SLE is primarily a disease of young women of childbearing age between 15 and 40 years old. However, the onset of the disease can range from infancy to old age. SLE affects approximately 1 in 2000 individuals in the general population, although the prevalence varies with race, ethnicity, and socioeconomic status.5 Females make up 80-90% of SLE patients, which affects as many as 1 in 1000 women. In North America and Northern Europe, there are about 40 cases of SLE per 100,000 population, with a higher incidence and tendency to more severe disease in black Americans and Hispanics .7 The prevalence in children and older adults is approximately 1 per 100,000. An investigation for drug-induced lupus should be considered in older patients with symptoms suspicious of SLE.
Although the precise immunologic events involved in the development of SLE remain poorly understood, a basic model of pathogenesis has emerged. In this model, an environmental trigger acts upon a genetically susceptible individual to create T-cell and B-cell defects that result in increased autoantibody production.1 The nature of the environmental trigger(s) initiating SLE is one of the least understood features of pathogenesis. Sex hormones, ultraviolet light exposure, drugs, and various infections modify the expression of this disease but may be quite distinct from a more general triggering agent. Many infections are thought to induce flares of activity in lupus, and some may actually predispose an individual to develop SLE. Such infections include parvovirus, CMV, and hepatitis C.1
CD4+ (helper) T cells are the driving forces in the pathogenesis of SLE.10 The specificities of many "self" antigens remain unknown. The evidence suggests, however, that B cells are driven by self antigens in a T-cell-dependent process that involves somatic mutation, affinity maturation, and IgM to IgG class switching.1
In population studies of SLE patients, the association of disease with specific class II major histocompatibility complex (MHC) alleles is weak and generally consistent only within a given ethnic group.1 For example, in Caucasians, there is an association of the human leukocyte antigen (HLA)-DR2 and/or (HLA)-DR3 with an increased incidence of SLE, but the relative risk is less than five times that of the general population.1 In contrast, class II MHC genes appear to exert a strong influence on the production of specific antinuclear antibodies.1 The antibody response to several lupus autoantigens is strongly associated with particular MHC class II (HLA-DQ) alleles as well as combinations of class II gene products.
Inherited complement deficiencies, some of which are determined by genes encoded within the MHC, show a powerful effect on disease susceptibility that is demonstrable across racial and ethnic groups. Complement genes for C4 (C4A and C4B) and C2 are encoded within the class III HLA region.8 A complete lack of the C4A and C4B genes leads to a lupus-like syndrome in most of the patients described. Homozygous C4A deficiency is present in 13-15% of SLE patients compared to less than 1% of healthy controls (relative risk, approximately 15-20 times the general population). Heterozygous C4A deficiency is present in 35-60% of SLE patients compared to 13-20% of healthy controls (relative risk, approximately 2-3). In patients with a homozygous C2 deficiency, nearly 20-30% will develop an autoimmune disease with features resembling SLE.8 Lupus is also associated with inherited complement deficiencies determined by genes encoded outside the MHC (e.g., Clq or Clrls) that cannot be explained by linked HLA genes. The mechanism by which complement deficiencies may influence the development of lupus is unknown but may involve defects in the clearance of immune complexes or viral particles.
An association of SLE with apoptosis (programmed cell death) was recently proposed.9 Several genes regulate apoptosis, including genes that inhibit (i.e., Bcl-2 gene) or promote (i.e., apoptosis-1/Fas gene) cell death. The abnormal expression of apoptosis-related genes (e.g., the over-expression of Bcl-2 or defects in the Fas gene) is associated with the development of lupus-like systemic autoimmune disease in animals.9 A soluble form of the Fas protein, an apoptosis-signaling receptor molecule on the surface of lymphocytes, was found in the sera of some patients with SLE.10 Injection of normal mice with this soluble form of the Fas protein resulted in the inhibition of apoptosis and the appearance of autoimmune features.11
The major immunologic feature recognized in patients with SLE is autoantibody production. These antibodies are directed to a host of self molecules found in the nucleus, cytoplasm, and the surface of cells. Serum antinuclear antibodies (ANA) directed against components of the cell nucleus are the most characteristic autoantibodies of SLE and are found in more than 95% of patients.12 Many different autoantibodies are detected in patients with SLE. The types and occurrences of these antibodies are shown in Table 2.
Clinical Manifestations
General or Constitutional Manifestations. Virtually all organ systems can be affected by SLE. Polyarthritis and dermatitis are the most common presenting symptoms and the most frequent clinical manifestations of SLE. (See Table 3.) Patients diagnosed with SLE may present with one or more disease features, including arthritis, thrombocytopenia, pericarditis, etc. (See Table 4.) These symptoms may persist or recur for months or years before the diagnosis is confirmed by the appearance of other features. Constitutional manifestations including malaise, overwhelming fatigue, fever, weight loss, and a variety of disturbances of cognition or affect, including anxiety and depression, are frequently described by patients as early symptoms.
Table 1. ACRDiagnostic Criteria for SLE*
CRITERIODEFINITION
1. Malar rash |
Fixed erythema, flat or raised, over the malar eminences, tending 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 |
Skin rash as a result of unusual reaction to sunlight, by patient history or physician observation |
4. Oral ulcers |
Oral or nasopharyngeal ulceration, usually painless, observed by physician |
5. Arthritis |
Nonerosive arthritis involving two or more peripheral joints, characterized by tenderness, swelling, or effusion |
6. Serositis |
a) Pleuritis-convincing history of pleuritic pain or rub heard by physician or evidence of pleural effusion OR |
b) Pericarditis-documented by ECG or rub or evidence of pericardial effusion | |
7. Renal disorder |
a) Persistent proteinuria greater than 0.5 grams per day or greater than 3+ if quantitation 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) |
9. Hematologic disorder |
a) Hemolytic anemia-with reticulocytosis OR |
b) Leukopenia-less than 4000/mm3 total on two or more occasions OR | |
c) Lymphopenia-less than 1500/mm3 on two or more occasions OR | |
d) Thrombocytopenia-less than 100,000/mm3 in the absence of offending drugs | |
10. Immunologic Disorder |
a) Positive LE cell preparation OR |
b) Anti-DNA: antibody to native DNA in abnormal titer OR | |
c) Anti-Sm: presence of antibody to Sm nuclear antigen OR | |
d) False positive serologic test for syphilis known to be positive for at least six months and confirmed by Treponema pallidum immobilization or fluorescent treponemal antibody absorption test | |
11. Antinuclear antibody |
An abnormal titer of antinuclear antibody by immunofluorescence or an equivalent assay at any time and in the absence of drugs known to be associated with "drug-induced lupus" syndrome |
*The proposed classification is based on 11 criteria. For the purpose of identifying patients in clinical studies, a person shall be said to have systemic lupus erythematosus if any four or more of the 11 criteria are present, serially or simultaneously, during any interval of observation.
Reprinted with permission of the American College of Rheumatology from: Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus (SLE). Arthritis Rheum 1982;25:1271-1277.
Cutaneous and Mucocutaneous Involvement. There are several types of skin involvement in SLE patients. The butterfly rash presents as an erythematous, elevated, pruritic, and sometimes painful lesion across the face in a malar distribution that, on biopsy, shows nonspecific inflammation, although immune deposits at the dermal-epidermal junction are seen by immunofluorescence. Approximately two-thirds of patients with SLE have photosensitivity, defined as a skin rash due to an unusual reaction to sunlight. Solar radiation may also exacerbate systemic disease activity. Reports indicate that up to 70% of patients with photosensitivity are positive for antiSSA (AntiRo) antibodies.13 Skin lesions on patients with SLE are either acute, subacute, or chronic. Some acute manifestations include bullous lesions and generalized erythema, which may or may not be photosensitive in nature.14 The clinical feature most characteristic of subacute cutaneous lupus is a superficial, nonindurated, and nonscarring photosensitivity-induced skin rash.15 In chronic cutaneous SLE, patients may have a discoid rash with scarring. The histologic examination of skin from affected areas in subacute cutaneous lupus erythematosus showed a relatively sparse, superficial inflammatory cell infiltrate. Patients with lupus usually show the classic dermal-epidermal junctional staining by immunofluorescence, or "lupus band," indicating an immune complex mediated process.16 The lupus band test is often positive in "unaffected" areas of the skin of patients with lupus and in patients with other diseases. According to the opinion of many rheumatologists, including the authors, the lupus band test is not cost-effective and produces little clinically useful information. Therefore, we do not routinely perform this biopsy.13 Some, however, argue that the lupus band test differentiates discoid lupus from SLE, because discoid lupus has a positive band test in only the skin lesions, whereas SLE will often have a positive test in both a rash and non-affected areas of skin.
Table 2. Major Autoantibodies in SLE
Ab |
% |
ANA |
> 95% |
Anti-dsDNA |
40-60% |
Anti-ssDNA |
70% |
Anti-Smith |
25-30% |
Anti-ribonuclear protein |
35% |
AntiSSA (Ro) |
35% |
AntiSSB (La) |
20% |
Anticardiolipin Abs |
75% |
Antihistone Abs |
70% |
Antiribosomal P Abs |
20% |
The mechanisms for the pathophysiologic effects of ultraviolet light are not fully understood. However, recent studies in patients with SLE showed that ultraviolet light may induce the synthesis of or facilitate translocation to the plasma membrane of antigens such as the SS-A(Ro), SS-B(La), Smith, and ribonucleoprotein. Increased expression of antigens related to SLE at the plasma membrane may provide an initial antigenic stimulus for the development of specific autoantibodies and be involved in an antibody-mediated or cytotoxic cell-mediated immune response.14 It is very important for patients with SLE to protect themselves from direct sunlight. Oral ulcers are usually painless and occur in up to 35% of patients with SLE.1 Raynaud's phenomenon occurs in 10-45% of patients with SLE, depending on the series, and is the result of vasospasm and vascular damage, especially apparent with the classical white, blue, and red color changes in the fingers.1 Alopecia is observed in up to 45% of SLE patients some time during their disease. It can occur also with some of the therapy for SLE. The hair loss may be diffuse or patchy, associated with discoid lesions.1
Table 3. The Most Common Presenting Manifestations of SLE
1. Arthritis/arthralgias |
55% |
2. Rash |
20% |
3. Nephritis |
5% |
4. Fever |
5% |
5. Pleuritis/Pericarditis |
5% |
6. Seizures |
3% |
7. Raynaud's |
2% |
8. Others |
5% |
Musculoskeletal Involvement. Arthralgia and arthritis occur in about 95% of patients with SLE. Approximately 75% of lupus patients develop true arthritis.17 The arthritis may be migratory or persistent and chronic and may include any joint, although typically the small joints of hands, wrists, and knees are symmetrically involved.10 SLE patients with arthritis usually do not develop joint erosions. Some patients develop metacarpal-phalangeal (MCP) and proximal interphalangeal (PIP) joint subluxations in the late stages of their disease, referred to as Jaccoud's arthritis.
Table 4. Approximate Cumulative Incidence of Clinical Manifestations in SLE Patients
Arthralgia or arthritis |
90% |
Rash |
85% |
Fever |
75% |
Renal involvement |
> 50% |
Pleuritis |
50% |
Pericarditis |
35% |
Alopecia |
30% |
CNS Symptoms |
25% |
Raynaud's phenomenon |
20% |
Oral and nasal ulcers |
20% |
Psychosis |
15% |
Features of SLE overlap with autoimmune diseases including rheumatoid arthritis, scleroderma, poly/dermatomyositis, and Sjogren's syndrome usually sequentially, although they can also exist concomitantly.1 The best known of these "overlap" syndromes is mixed connective tissue disease (MCTD). MCTD can have findings of any of the five diseases mentioned above but originally was described with features of SLE, poly/dermatomyositis, and scleroderma and, by definition, has to have circulating antibodies to the ribonucleoprotein, U1 RNP. Patients with MCTD are less likely to develop nephritis than those with SLE but tend to develop scleroderma changes late in their course. Overlapping features of SLE with rheumatoid arthritis are seen in a few patients. The coexistence of SLE and RA may be determined by having clinical criteria for both diseases including radiological findings.18
Table 5. World Health Organization Classification of Lupus
Histology |
Prognosis |
I Normal |
Excellent |
II Mesangial lupus nephritis |
Good |
III Focal proliferative lupus nephritis |
Moderate |
IV Diffuse proliferative glomerulonephritis |
Poor |
V Membraneous glomerulonephritis |
Moderate |
VI Glomerulosclerosis |
Poor |
Patients with SLE commonly complain of muscle pain and weakness. Although true myositis may coexist with SLE, fibromyalgia, drug-induced myopathy secondary to corticosteroids, antimalarials, and other drugs, or coexisting thyroid disease may cause muscular symptoms.10
Renal Involvement. The kidney is the most commonly involved internal organ in patients with SLE. Approximately 50-75% of renal biopsies from SLE patients reported in several series show evidence of nephritis.19 Clinically active renal disease is manifested by the presence of proteinuria (> 500 mg/24 hours), cellular casts, hematuria (> 5 RBCs/hpf), or pyuria (> 5 WBCs/hpf) in the absence of other causes of kidney damage.
Table 6. Nervous System Involvement of SLE
Seizure disorder
Psychosis
Depression
Cerebrovascular accident
Movement disorder
Headache
Pseudotumor cerebri
Transverse myelitis
Mononeuritis multiplex
Guillain-Barré syndrome
Organic brain syndrome
Cranial nerve palsy
Peripheral neuropathy
Aseptic meningitis
Hypothalamic dysfunction
Myasthenia
Eaton-Lambert syndrome
Cerebellar ataxia
Thrombotic thrombocytopenic purpura
The World Health Organization (WHO) classification of SLE (Table 5) lists the types of glomerulonephritis found in patients with SLE.20 According to statistics from WHO, only three out of 148 patients with SLE studied had truly normal kidney biopsies, suggesting that most have varying degrees of renal pathology. Lupus nephritis may also involve the kidney interstitium. The pathogenesis of lupus nephritis includes precipitation of immune complexes with autoantibodies that react with DNA (anti-dsDNA antibodies) and other cellular components in the glomeruli and interstitium of the kidney.21 Studies correlating the type and severity of nephritis revealed several features that appear to promote pathogenecity, including the quantity of circulating antibodies, charge, class, isotype, idiotype, avidity for DNA, and efficiency of complement fixation.21 Furthermore, cross-reactivity of anti-DNA autoantibodies with glomerular cell surface antigens, as well as with normal components of basement membrane and mesangial matrix, probably promotes immune complex formation and influences the location of these deposits within the glomerulus.22
Neuropsychiatric Involvement. Neuropsychiatric involvement of patients with SLE (Table 6) ranges from simple headache to CNS vasculitis. Other unusual manifestations of CNS lupus include Parkinsonism, cerebellar ataxia, pseudotumor cerebrae, hypothalamic dysfunction, aseptic meningitis (related to NSAID use), myasthenia-like syndrome, Eaton-Lambert syndrome, and thrombotic thrombocytopenic purpura. Peripheral nervous system involvement of SLE is also noted in approximately 10% of patients and includes sensory or motor myopathies, Guillain Barré-like syndrome, and mononeuritis multiplex.
Table 7. Drugs Known to Cause a Lupus-Like Syndrome
Procainamide
Hydralazine
Isoniazide
Hydantoins
Chlorpromazine
Methyldopa
D-penicillamine
Interferon-r
The pathogenesis of neuropsychiatric SLE includes vasculitic-induced blood vessel occlusion, antibody against brain tissue, hypercoagulable status due to antiphospholipid antibodies, and other secondary causes such as infection, metabolic derangement, and side effects of drugs that are used for treatment of SLE.10
Recently, circulating antineuronal and anti-ribosomal P antibodies were found in many patients with CNS lupus.23 The pathogenic significance of these findings needs further study.
Hematological Manifestation. Anemia, leukopenia, and thrombocytopenia are frequent manifestations of SLE. Patients with SLE often have normocytic normochromic anemia. Coomb's positive hemolytic anemia is frequently present. Circulating antierythropoietin antibodies were recently reported as a possible mechanism of anemia in SLE patients.24
Leukopenia with white blood cell counts of less than 4000/mm3 or lymphopenia with cell counts less than 1500/mm3 on two or more occasions are part of the diagnostic criteria of SLE. (See Table 1.) However, other causes of decreased WBC counts including malignancy, infection, and drug-induced leukopenia should be excluded before attributing the low WBC count to SLE.
Thrombocytopenia with a platelet count of less than 100,000/mm3 in the absence of other causes is found in up to 25% of SLE patients. Antiplatelet autoantibodies bind to one or more surface glycoproteins (usually the glycoprotein II-IIIa complex). The antibody-coated platelets are ingested in the spleen, liver, lymph nodes, and bone marrow by macrophages with receptors for the Fc region of immunoglobulin. A number of patients with SLE and thrombocytopenia have circulating antiphospholipid antibodies and have a co-existing antiphospholipid syndrome.25 Spontaneous bleeding is rare in patients with platelet counts of more than 5000/mm3. However, thrombocytopenia is often a marker of severe disease with poor prognosis.26 It is important to recognize that a positive antinuclear antibody (ANA) test is also reported in up to 30% of patients with chronic idiopathic thrombocytopenic purpura.27
Other Clinical Manifestations of SLE. SLE affects the heart in several ways, including pericarditis, myocarditis, coronary artery disease, and endocarditis. Pericarditis is the most common cardiac manifestation of SLE, occurring in about 20-30% of patients, and usually presents with mid-anterior chest pain. Myocarditis, which is probably vasculitic, is suspected when SLE patients have cardiomegaly, arrhythmias, or conduction defects and usually co-exists with pericarditis during the active phases of SLE. Sterile vegetations of the heart valves, or Liebman Sacks' endocarditis, is a less common cardiac manifestation of SLE. It was recently suggested that Liebman Sacks' endocarditis is often a part of the antiphospholipid syndrome. The prevalence of Liebman Sacks' endocarditis has decreased since treatment with corticosteroids was introduced in the 1950s. It is important to differentiate lupus endocarditis from infective endocarditis. It is also important to prophylactically treat patients with lupus endocarditis with antibiotics when they have any medical or dental procedure. Coronary artery disease is becoming more common in patients with SLE, because they are living longer and because of the effects of high doses of corticosteroids used to treat their disease.28 Coronary artery vasculitis is not commonly found in SLE patients.
The pulmonary manifestations of systemic lupus include pneumonitis, pulmonary hemorrhage, hypertension, and embolism. Lupus pneumonitis is a clinical dilemma that requires careful diagnosis, because it must be differentiated from an infectious pneumonia. It may at times be necessary to treat patients both with corticosteroids and antibiotics until the etiology is clear. Pulmonary hemorrhage from vasculitis is associated with a 50-60% mortality rate and is a true medical emergency.29 Pulmonary hypertension is more commonly associated with long-term restrictive lung disease and Raynaud's syndrome.
Gastrointestinal symptoms in patients with SLE are relatively common and present as abdominal pain, anorexia, nausea, and/or vomiting. Peritoneal inflammation is the most likely cause of GI symptoms, but mesenteric vasculitis or pancreatitis are dangerous complications of SLE and need to be considered in the presence of abdominal symptoms.30 Abdominal pain may be masked in patients being treated with cortico-steroids and may perforate a viscous with very few symptoms to alert the physician of serious complications.
Table 8. Adverse Effects of Glucocorticoid
Infection
Osteoporosis
Avascular Necrosis
Peptic Ulceration with Combination Treatment of NSAIDs
Hypertension
Coronary Artery Disease
Cataracts
Weight Gain
Mood Disturbance
Glucose Intolerance
Laboratory Findings
The serum antinuclear antibody test (ANA) is positive in more than 95% of patients with SLE. The ANA is the most sensitive laboratory test for SLE and, therefore, is the most effective for a screening test for lupus. Since the ANA is not very specific, it is most valuable when it is negative, because its absence almost rules out SLE as a diagnosis.30 In contrast, antibodies to the Smith antigen (anti-Sm antibodies) and the anti-native or anti-ds DNA antibodies are highly specific for SLE and, therefore, make very good confirmatory tests for the diagnosis of SLE.30 Table 2 lists a number of the antibodies found in SLE. AntiSSA (Anti-Ro) antibodies are often detected in Sjogren's syndrome, and also in about 30% of patients with SLE. AntiSSA antibodies are very important to detect in pregnant patients with lupus, because these antibodies are frequently associated with neonatal heart block, requiring much closer monitoring of the fetus during pregnancy.31 Infants of mothers with antiSSA antibodies may also have transient features of SLE, including a rash, hematologic abnormalities of SLE, and/or abnormally elevated liver function tests. Anti-SSB (Anti-La) antibodies, also seen in Sjogren's, are found in patients with SLE in 20-30% of cases.
It is very important to screen patients with SLE for the antiphospholipid syndrome, because of the potentially serious consequences of thromboembolic events associated with this condition. It is important to test the patient for anticardiolipin antibodies (especially the IgG antibodies), as they are most often associated with thromboembolic events. Measuring serum for the presence of the lupus anticoagulant may diagnose other patients with antiphospholipid syndrome not recognized with the anticardiolipin antibody test. In some cases, anticardiolipin antibodies and the lupus anticoagulant may be negative, but the serum anti-b-2 glycoprotein I antibodies may be present and are very significant for a high risk of thromboembolic events.32 The diagnosis of the antiphospholipid syndrome is not only associated with increased thromboembolic events but also spontaneous abortions and thrombocytopenia.
One index of the activity of SLE that can be monitored is measuring serum complement levels, which may be depressed. A decreased serum level of C3, C4, or CH50, along with a rising titer of anti-double-stranded DNA antibodies, may warn the physician of an impending SLE flare, which should result in more frequent monitoring of the patient and earlier treatment of a potentially serious flare.33
Other tests that are important to do in systemic lupus include a CBC, which may detect a depressed white blood cell (WBC) count and evidence of hemolytic anemia or thrombocytopenia. A Coomb's test may help in detecting hemolytic anemia associated with SLE. Anti-histone antibodies are present in the sera of 95% of patients with drug-induced lupus. The most common offending drugs include procainamide, hydralazine, and isoniazide.34 Many other drugs are also suspected to cause drug-induced lupus. (See Table 7.) The symptoms of drug-induced lupus are milder but similar to those in patients with SLE, except that the kidney is not usually involved. Stopping the offending drug usually resolves the symptoms. There are other antibodies measured in patients with SLE that have more research value than clinical significance.1
Diagnosis of SLE
The diagnosis of SLE should be made on a clinical basis and supported by specific laboratory tests. The key to the diagnosis of SLE in a patient in your office is to know the American College of Rheumatology (ACR) revised 1982 criteria for the diagnosis of systemic lupus.6 (See Table 1.) If the patient has four of these criteria confirmed, either on examination or historically, SLE is the most likely diagnosis. Occasionally, however, one can be fooled, and a patient with other diseases, such as hepatitis, subacute bacterial endocarditis (SBE), or other autoimmune diseases may demonstrate four criteria for SLE. In more than 95% of the cases, however, SLE will be the correct diagnosis. In a recent news bulletin, the ACR recommended that the tenth criterion drop the LE prep and add the presence of one of the serum antiphospholipid antibodies.
There are other clinical features also important to recognize in SLE that help with diagnosis. Table 3 outlines the most common presenting features of SLE. The differential diagnosis one must consider on presentation of a patient suspected to have SLE is immense. One can be easily confused, if unable to fit all the multisystem signs and symptoms together into the syndrome of SLE. Recognizing that a patient has a multisystems disease narrows the choices one has to pick from, such as RA, one of the vasculidities, other autoimmune diseases, malignancies, fibromyalgia, and infectious diseases, such as SBE, HIV, hepatitis B or C, etc. If the ANA test is negative, one can almost rule out SLE. However, if the ANA is positive, the rest of the ACR criteria and other clinical findings need to be applied to help select SLE from your differential diagnosis. A patient may not have four criteria but can appear to have SLE. This type of patient is often given the diagnosis of a "lupus-like syndrome." Rarely a patient may be diagnosed with "ANA-negative SLE." Expert opinion is needed to help with this diagnosis.
Management of SLE
It is sobering to note that the leading cause of death in SLE is from infection, which usually has an iatrogenic component.35 It is extremely important not to undertreat or overtreat SLE. A rule of thumb in treatment of SLE is that mild disease requires mild treatment, and severe, catastrophic disease requires heroic treatment. This requires a great deal of experience in managing this disease, and even then, there are treatment failures. Complications of treatment, including infections and drug toxicities, or failure to treat adequately in a timely manner, are responsible for most of the morbidity and mortality seen in SLE. The inappropriate use of cortico-steroids often represents the greatest threat to a patient's well being of any of the drugs used in treatment of lupus. The major side effects of corticosteroids are listed in Table 8. When using high doses of corticosteroids for serious complications of SLE, our goal as clinicians should be to get the patient on the lowest effective dose as soon as possible. If one can control SLE adequately, it is often desirable to have the patient on an alternate-day schedule within 4-6 weeks of the initiation of treatment. The use of concurrent drugs, such as hydroxychloroquine, azathioprine, methotrexate, cyclosporine, cyclophosphamide, and others, if indicated, will often help limit the dose of corticosteroids.36 One must weigh the potential toxicities of each of these drugs in determining the "best" therapeutic regimen for each patient.
Cases of severe nephritis, central nervous system involvement, pulmonary hemorrhage, and other forms of systemic vasculitis require the rapid initiation of high doses of cortico-steroids with cytotoxic medications, especially cyclophosphamide.33
Skin and Mucocutaneous Lesions. Protection of the skin from ultraviolet light is very important and includes such measures as applying sunblock to prevent photosensitivity reactions, and using umbrellas, wearing hats and long sleeve shirts, etc. to prevent sunlight from striking the skin. Topical cortico-steroid creams and hydroxychloroquine are effective in treating some of the rashes of systemic lupus. Intralesional injections of corticosteroids can be helpful for discoid lupus. Raynaud's phenomenon is usually relatively mild and seasonal in SLE. The more simple cases can be treated by keeping hands and feet warm with gloves and socks and taking calcium channel blockers, especially nifedipine.37 Mucocutaneous lesions, if painful, can be treated with topical corticosteroids available in a dental paste.
Musculoskeletal Lupus. Arthritis and arthralgias generally should be treated with nonsteroidal anti-inflammatory drugs (NSAIDs) and hydroxychloroquine, if needed. Corticosteroids for the arthritis treatment alone adds more toxic side effects than are warranted in most cases. If the arthritis is severe, low doses of prednisone (7.5 mg or less) may be necessary and ancillary to steroid-sparing drugs like methotrexate or azathioprine similar to the treatment of rheumatoid arthritis.36
Cardiopulmonary Lupus. Pleurisy and/or pericarditis (polyserositis) can often be treated symptomatically with NSAIDs, but one may at times need to use low to moderate doses of corticosteroids in the range of up to 0.5 mg/kg/d of prednisone until symptoms clear.33 For severe pericarditis or pleurisy with pleural effusion, intravenous pulse methylprednisolone of 1000 mg daily for 2-3 days followed by oral prednisone 1-2 mg/kg/d should be given.33 The dose of prednisone should be slowly tapered back to the maintenance dose watching closely for exacerbations of the symptoms. Frequent flares of the polyserositis may require steroid-sparing treatment with azathioprine or methotrexate.
SLE-related pulmonary hemorrhage requires heroic intervention because of a 60% mortality rate.29 Treatment with pulse methylprednisilone 1000 mg/d along with cyclophosphamide, ventilator assistance in an ICU setting, intravenous immunoglobulin, and apheresis are among the modalities that have been tried.
Interstitial lung disease either from the SLE or the drugs used in the treatment of lupus occurs occasionally. An open lung biopsy may be needed to differentiate between an infectious agent and an autoimmune mediated process. The acute process is treated with high doses of corticosteroids often followed by cytotoxic drugs used in other high-risk manifestations of lupus.29
Pulmonary hypertension and myocarditis are rare but must be anticipated and treated appropriately similarly to other forms of severe SLE previously mentioned.
Coronary artery disease is becoming more common as lupus patients are living longer.28 Corticosteroids are thought to be a major contributor to early atherosclerosis and may be a good reason to use cytotoxic drugs to limit the amount of corticosteroids to low doses and alternate-day therapy where the risk of long-term complications outweighs the risks of azathioprine, methotrexate, cyclophosphamide, and similar drugs.
Kidneys. Mesangial lesions (WHO Class II) usually do not cause significant signs or symptoms of nephritis and are not regularly treated. Lupus nephritis with focal glomerulonephritis (WHO Class III) may only require low-dose prednisone in the neighborhood of 10-15 mg every other day. If low-dose, alternate-day corticosteroids are not effective in controlling the nephritis, most studies support the use of azathioprine long term to limit the dose of corticosteroids used and to preserve kidney function. However, patients with severe kidney involvement, especially diffuse, proliferative glomerulonephritis (WHO Class IV), the most aggressive form of lupus nephritis, may need to be started on therapy with 1 g of methylprednisolone IV daily for about 3-5 days to rapidly decrease the inflammatory activity in the glomeruli.37 These patients should then be treated with approximately 80-120 mg of prednisone daily in divided doses, and I would argue for a goal to get the patient on alternate day therapy (even if it is 120 mg every other day) by 4-6 weeks of treatment. The recognized definitive treatment of lupus nephritis is pulse IV cyclophosphamide in a dose of 0.5-1.0 g/m2 body surface area (10-20 mg/kg) once monthly for six months and often every three months thereafter indefinitely.35 This treatment protocol has markedly reduced end-stage renal disease in systemic lupus from 75% of patients in four years on prednisone alone to less than 10% in 10- to 20-year follow-up studies. The IV pulse of cyclophosphamide compared with oral administration markedly decreases the toxicity of this drug, including hemorrhagic cystitis, infection, sterility, etc.37 The addition of mesna in a dose equal to cyclophosphamide post-cyclophosphamide infusion also limits hemorrhagic cystitis.
Other experimental therapies for diffuse proliferative lupus nephritis include plasmapheresis, which may acutely reduce the antibody load and, consequently, disease activity but results in rapid rebound of anti-DNA antibody levels and disease activity, if not supplemented by corticosteroids and cyclophosphamide.38 Intravenous immunoglobulin in small series was effective in life-threatening situations.39 Cyclosporine A (3-5 mg/kg) also appears to be effective, especially in treating the nephrotic syndrome associated with membranous glomerulonephritis (WHO Class V).40 Cyclosporine may be added to the long-term treatment protocols of lupus nephritis in the future, whereas plasmapheresis and IV immunoglobulin are far too expensive and of questionable long-term value in the treatment of lupus nephritis and are therefore usually saved for life-threatening, catastrophic complications of lupus.
Attention to the treatment of hypertension by the clinician is very important to the long-term outcome of lupus nephritis. However, the nephritis worsens in some patients and they develop end-stage kidney disease with glomerulosclerosis (WHO Class VI) and ultimately start dialysis. These patients become candidates for kidney transplant and do fairly well, even though the newly transplanted kidney may occasionally develop lupus nephritis.41 Therefore, it is often important to follow the patient's anti-double-stranded DNA antibodies and serum complement levels to help predict whether the patient may have a flare of his lupus nephritis in the near future and treat the patient aggressively.42
Nervous System. CNS lupus that is catastrophic in nature can be managed by basically the same treatment as for severe, catastrophic lupus nephritis, with high doses of corticosteroids and with IV cyclophosphamide. The psychosis of CNS lupus responds to corticosteroids. However, high doses of cortico-steroids can also cause a psychosis that is difficult to differentiate in patients treated for SLE. Psychotropic drugs for neuropsychiatric lupus on a long-term basis may be needed, such as haloperidol and/or chlorpromazine for severely agitated patients.43 Patients with chronic organic brain syndrome from CNS vasculitis respond poorly to aggressive therapy. They would be better managed by early recognition and aggressive treatment when immunologic features are still present. Seizure disorders in lupus can be treated with anticonvulsants, such as phenytoin but also may require corticosteroids in the initial acute phases of CNS lupus.
Strokes occur from several mechanisms in about 5% of patients with lupus at some time during their disease.44 Strokes are often a result of arterial thrombosis, a thromboembolism due to vegetations breaking loose in Liebman Sacks' endocarditis. In patients with SLE, stroke is most commonly associated with the antiphospholipid syndrome, which will be discussed later. Patients with SLE and antiphospholipid syndrome may also develop chorea, which resolves spontaneously within a few weeks. Transverse myelitis associated with loss of urinary or anal sphincter control and paralysis occurs uncommonly in patients with lupus, most often coexisting with the antiphospholipid syndrome. Treatment of transverse myelitis is with high doses of corticosteroids and cytotoxic agents, especially with cyclophosphamide. The treatment is not very successful at reversing the neurological findings but may help arrest the progress of the disease.
Hematologic Abnormalities in SLE. Anemia occurs often in patients with active SLE. The cause of this anemia may be blood loss (i.e., NSAID-induced GI blood loss), anemia of chronic disease, immunosuppressive treatment, and hemolytic anemia (often Coombs positive). The treatment of the anemia needs to be aimed at the underlying cause, and if obscure, a bone marrow aspiration and biopsy may need to be done. Mild or moderate hemolytic anemia usually responds to cortico-steroids and, if needed, azathioprine to reduce the dose of the corticosteroids to acceptable levels.33 Danocrine is an alternative drug for hemolytic anemia, but masculinizing effects limit its use. Severe hemolytic anemia is treated similarly to other forms of catastrophic SLE.
Leukopenias caused by SLE usually are not low enough and do not need to be treated, but medication-induced neutropenia may require granulocyte-monocyte-colony stimulating factor (GM-CSF) or similar means to increase WBCs.
Thrombocytopenia below 35,000 counts may need treatment with corticosteroids, and if severe and life-threatening, is treated similarly to severe hemolytic anemia. The hemolysis may also require IV immunoglobulin and ultimately a splenectomy, if other treatments fail.33
Pregnancy and Lupus. It is best for patients with SLE to have their disease under good control for several months before contemplating pregnancy. SLE will flare in about 60% of cases during pregnancy, although it is argued by some investigators that this is not substantially different than the flare rate for non-pregnant lupus patients over an equivalent period of time.45 Oral contraception is controversial for SLE patients, but some feel it is safer than pregnancy. However, all pregnancies in patients with SLE should be considered high risk and followed regularly by a trained high-risk obstetrician. Premature delivery occurs in about 45% of pregnancies in SLE patients, and loss of the fetus occurs in 15%.45 Of special concern are patients positive for circulating antiSSA antibodies, the antiphospholipid syndrome, and patients with active lupus needing cytotoxic medications. Frequent monitoring of the heart of the fetus with four chamber echocardiogram for the development of heart block is necessary for those positive for antiSSA antibodies. The antiphospholipid syndrome will be discussed below.
Patients should be strongly urged not to get pregnant until discontinuing cyclophosphamide and methotrexate for three months because these medications are potentially severely detrimental to the fetus. NSAIDs should not be used except for a few days at a time in the second and third trimesters and not at all near the time of birth, because of their effect on the fetal ductus arteriosis. Severe flares of SLE should be treated with high doses of corticosteroids during pregnancy and, if necessary, supplemented with azathioprine. Intravenous cyclophosphamide should not be used, especially in the first trimester, except in severe life-threatening situations.
Antiphospholipid Syndrome. The antiphospholipid syndrome, as mentioned above, is frequently associated with the manifestations of CNS lupus, particularly stroke, chorea, and transverse myelitis.46 The antiphospholipid syndrome is also usually present in other thromboembolic complications of SLE. Patients who are diagnosed with the antiphospholipid syndrome must be anticoagulated and their protime maintained at an INR of between 3 and 4. Even then, some of these patients may continue to thrombose multiple vessels. Spontaneous abortions in female patients with SLE are most frequently associated with the antiphospholipid syndrome. Patients with a history of spontaneous abortions who become pregnant and have antiphospholipid syndrome should be treated with aspirin and heparin, approximately 10,000-20,000 units subcutaneously twice a day, from early pregnancy until the fetus is delivered.47 Some authors recommend adding corticosteroids (15-20 mg/d), if the serum level of anticardiolipin antibodies rises suddenly. If a pregnant patient with lupus and the antiphospholipid syndrome has not experienced fetal loss in the past, some would argue that corticosteroids in moderate doses and aspirin may improve the fetal outcome.48 However, in those patients with a history of miscarriages, subcutaneous heparin-preferably low molecular weight heparin to limit osteoporosis, is the drug of choice.
Experimental Treatments for SLE. There are experimental therapies used with varying degrees of success in systemic lupus, especially in patients with rather severe, catastrophic forms of SLE. A number of new potential therapeutic interventions are being tested by research laboratories, including vaccinations, tolerizing procedures, antibodies against surface molecules on B and T cells, and other cytotoxic drugs. IV gammaglobulin is sometimes used in patients with SLE who have rather severe thrombocytopenia, hemolytic anemia, and other major complications of lupus.33 This treatment appears to have been successful in many cases, but double-blind studies proving its efficacy have not as yet been published. The manipulation of sex hormone levels is used, especially in thrombocytopenia, with the use of danazol. In open trials, dihydroepiandrosterone (DHEA) was used in mild to moderate lupus with some success.49
The Prognosis
The prognosis of patients with SLE has improved considerably since the early 1950s, with the five-year survival rate at about 85%, 10-year survival at 75%, and 15-year survival at about 65%.50 Prior to 1950, the four-year survival rate was at about 50%. Changes in treatment of SLE since the 1950s are largely responsible for this improvement. However, SLE still remains a very dangerous and fatal disease, if not managed appropriately.
Summary
In summary, systemic lupus erythematosus is a disease of the immune system manifested by production of numerous autoantibodies, some of which, including anti-double-stranded DNA antibodies, are pathogenic for disease manifestations of some features of lupus. SLE affects virtually all organ systems and, in its moderate to severe forms, needs very close attention by physicians familiar with the disease and its complications. It is important to know the diagnostic criteria for SLE in order to recognize the disease, especially in its earlier forms when it is much more treatable. SLE remains one of the most fascinating and troubling diseases facing physicians.
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