37.

Chapter 30 Systemic Lupus Erythematosus

Manual of Rheumatology and Outpatient Orthopedic Disorders

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Chapter 30 Systemic Lupus Erythematosus

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Jane E. Salmon and Robert P. Kimberly

Epidemiology
Genetics
Pathogenesis
Clinical presentation
Laboratory abnormalities
Differential diagnosis
Treatment
Prognosis

Systemic lupus erythematosus (SLE) is a multisystem disease with a spectrum of clinical manifestations and a variable course characterized by exacerbations and remissions. Lupus is marked by both humoral and cellular immunologic abnormalities, including multiple auto-antibodies that may participate in tissue injury . Antinuclear antibodies (ANAs), especially those to native DNA, are common immunologic abnormalities found in the disease. During the nineteenth century, lupus was considered to be a skin disease. By some accounts, the erosive nature of some of the skin lesions seemed to resemble the damage inflicted by the bite of a wolf, which may have led to the name lupus. In 1872, Moriz Kaposi described systemic symptoms in association with cutaneous disease. At the turn of the century, Sir William Osler described arthritis and visceral manifestations in conjunction with polymorphic skin lesions. The presence of circulating immunologic factors became apparent about 50 years later with the discovery of the LE cell phenomenon by Hargraves in 1948, the recognition of the LE factor as an ANA in 1953, and the identification of antibodies to native DNA in 1956. Identification and characterization of abnormal auto-antibodies continue to be major areas of clinical and immunochemical interest. The development of sensitive laboratory tests for auto-antibodies has enabled the recognition of milder forms of SLE, with a consequent change in both reported prevalence and prognosis. The broad clinical spectrum of SLE challenges the diagnostic and therapeutic acumen of the physician .

I. Epidemiology

1. Sex. A female-to-male ratio of 9:1 is seen in most series of adult patients . The female predominance is less striking in childhood SLE (disease onset preceding puberty) and in elderly SLE patients.
2. Age. First symptoms usually occur between the second and fourth decades of life but may be seen in any age group . The presentation of SLE in the elderly (as much as 10% of the total lupus population in some series) may differ from that in younger patients.
3. Ethnic distribution. Although lupus occurs in all races, its prevalence is not equally distributed among all groups. SLE occurs more commonly in the United States than in England and more often in blacks than in whites. Hispanic and black patients have been noted to have more severe disease. The average annual incidence in the United States is approximately 27.5 per million population for female whites and 75.4 per million for female blacks. The reported prevalence figures for women vary widely from 1 in 1,000 to 1 in 10,000.

II. Genetics. The presence of a genetic component in SLE is supported by family studies.

1. Clinical disease. Family members of SLE patients are more likely to have lupus or another connective tissue disease. The risk for development of SLE in a sibling of persons affected by SLE is approximately 20 times that in the general population. Concordance of disease among monozygotic twin pairs may be as high as 50% but is not complete. Fraternal twins, with a concordance rate of 2% to 5%, do not have a higher frequency of SLE than other first-degree relatives do. Asymptomatic (or healthy ) family members are more likely to have a false-positive test result for syphilis, ANAs, anti-lymphocyte antibodies, and hypergammaglobulinemia.
2. Histocompatibility studies. Lupus and lupuslike syndromes are associated with inherited abnormalities of the major histocompatibility complex (MHC) class III genes for complement components (most commonly the C4 null allele, but also deficiencies of C2; deficiencies of other complement components are rare). Although the strength of the association varies by ethnicity , SLE is associated with the serologically determined MHC class II allo-antigens HLA-DR2 and HLA-DR3. The association with HLA-DR2 reflects the DR2 allele DRB1*1501 in white and Asian populations and the unique DRB1*1503 allele in African Americans. HLA-DR3 is primarily associated with lupus patients of European ancestry.
3. Non-major histocompatibility complex genes. Genetic variants of opsonins (mannose binding protein, C-reactive protein, complement components), opsonin receptors (complement receptors, immunoglobulin receptors), lymphocyte cell surface molecules, and cytokine genes (tumor necrosis factor-alpha, interleukin-1, interleukin-10) have been associated with SLE. Fc g R are important in immune complex clearance. Allelic variants of Fc g R, which differ in their capacities to bind immunoglobulin G (IgG), alter the function of mononuclear phagocytes and thereby provide a mechanism of inherited differences in immune complex handling. The low IgG binding alleles of Fc g R have been associated with increased risk for lupus nephritis.

III. Pathogenesis

1. Pathology. Although no histologic feature is pathognomonic for SLE, several features are very suggestive: (a) fibrinoid necrosis and degeneration of blood vessels and connective tissue; (b) the hematoxylin body (the in vivo LE cell phenomenon); (c) onion skin thickening of the arterioles of the spleen; and (d) Libman-Sacks verrucous endocarditis.
   1. Histopathology. Routine histologic examination of tissue specimens reveals a broad range of findings.
      1. Skin biopsy may demonstrate a leukocytoclastic angiitis, especially in palpable purpuric lesions. The typical lupus rash usually shows epidermal thinning, liquefactive degeneration of the basal layer with dermal-epidermal junction disruption, and lymphocytic infiltration of the dermis. Rheumatoid-like nodules with palisading giant cells are uncommon, and panniculitis is rare.
      2. Synovium. Synovial biopsies may show fibrinous villous synovitis. The presence of pannus formation or bone and cartilage erosions is rare.
      3. Muscle biopsies usually show a nonspecific perivascular mononuclear infiltrate, but true muscle necrosis, as seen in polymyositis, can occur. Muscle biopsy may be helpful in evaluating the possibility of steroid-induced myopathy or chloroquine-induced myopathy, a rare entity in patients taking antimalarial agents .
      4. Kidney. The kidney has been the most intensively studied organ in SLE. The entire range of glomerulonephritis (membranous, mesangial, proliferative, and membranoproliferative) is seen (Table 30-1). Crescentic and necrotizing vasculitic lesions may be found. Interstitial abnormalities are often present. No single renal lesion is diagnostic of SLE. Tubuloreticular structures are not restricted to SLE. In general, renal biopsy provides one indicator of prognosis, characterizing patients with diffuse membranoproliferative lesions as having the poorest 5-year survival (40% to 85% depending on the series). Marked chronic changes (glomerular sclerosis, fibrous crescents, interstitial fibrosis, tubular atrophy) indicate a poor prognosis. Recognition that the histologic class of the biopsy specimen may not be static and may either deteriorate or improve has emphasized the need for defining renal disease activity sequentially.
         
         
         

         
         

         Table 30-1. World Health Organization classification of lupus nephritis

         
         
         
      5. Central nervous system. Multifocal cerebral cortical microinfarcts associated with microvascular injury are the most common abnormalities associated with neuropsychiatic SLE. Central nervous system lesions usually reflect vascular occlusion as a consequence of noninflammatory vasculopathy, leukoagglutination, thrombosis, vasculitis (rarely), and antibody-mediated neuronal injury. Normal brain tissue is often present despite clinical abnormalities. Cytoid bodies, seen as white fluffy exudates on funduscopic examination, represent superficial retinal ischemia.
      6. Other viscera. Other visceral pathologic findings include Libman-Sacks verrucous endocarditis with redundant mitral valvular leaflets and lengthened chordae tendineae, pulmonary fibrosis, and nonspecific pleural thickening. Necrotizing vasculitis may be present in the viscera and lead to secondary events, including bowel infarction, myocardial infarction, pancreatitis , and accelerated atherosclerosis. In the spleen, the concentric periarterial fibrosis of small arteries (onion skin lesions) may be an end-stage consequence of earlier vasculitis.
   2. Immunopathology
      1. Skin. Immunofluorescence shows deposits of immunoglobulins and complement at the dermal-epidermal junction (lupus band test) in 80% to 100% of lesional and 36% to 100% of nonlesional skin specimens. Attempts to correlate a positive lupus band test result with active SLE or the presence of lupus nephritis have given inconsistent results. Positive lupus band test results are not specific for lupus; they are commonly associated with bullous pemphigoid and dermatitis herpetiformis (IgA). Dermal-epidermal immunofluorescence may also be seen in rheumatoid arthritis, scleroderma, dermatomyositis, lepromatous leprosy, multiple sclerosis, cystic fibrosis, chronic active hepatitis, primary biliary cirrhosis, amyloidosis, and, according to some reports , normal subjects.
      2. Kidney. Glomerular immunofluorescence to determine the distribution, pattern, and density of immunoglobulin, immunoglobulin class, and complement components does not appear to have prognostic or therapeutic significance. The presence of immunofluorescence for immunoglobulin or complement is not restricted to SLE; it is, however, compatible with immune complex-mediated disease.
2. Immunology
   1. Humoral immunity. Hyperactivity of the humoral component of immunologic responsiveness is manifested by hypergammaglobulinemia, auto-antibodies, and circulating immune complexes.
      1. Various auto-antibodies may contribute to tissue injury. Attempts to correlate specific clinical patterns of disease with specific types of auto-antibodies have been partially successful. For example, anti-DNA antibodies have been found in renal glomerular lesions. Sicca syndrome with SLE has been associated with La (SS-B) antibodies. Ro (SS-A) antibodies have been associated with neonatal lupus, congenital complete heart block, and subacute cutaneous lupus. The lupus anticoagulant and anti-cardiolipin antibodies are associated with thrombosis, thrombocytopenia, and increased fetal wastage. Although the titer of ANAs does not necessarily correlate with disease activity, the levels of anti-DNA antibodies may vary with clinical disease. Because results vary, this test cannot be used as the sole guide to therapy .
      2. Circulating immune complexes are commonly found in active SLE and are often associated with hypocomplementemia. Immune complex deposits are found in many tissues. Isolated determinations of circulating complexes do not consistently correlate with disease activity. Sequential patterns of change may be of value in individual patients.
   2. Cellular immunity. SLE is characterized by lymphopenia and often by monocytosis. The normal complex immunoregulatory balance among cells is lost. Anergy, evidenced by diminished delayed hypersensitivity skin testing reactions , is common. Immunoglobulin-producing B cells are hyperactive. T-cell subsets are altered , and mononuclear phagocytes elaborate increased amounts of various cytokines. The primary defect has not been identified.
3. Provocative agents. Although the etiologic agent(s) in SLE have not been identified, several factors that may exacerbate the disease are known.
   1. Ultraviolet light. Sun exposure may precipitate either the onset or a flare of clinical disease, causing both dermatologic and systemic manifestations in about one-third of patients. Because complete avoidance of the sun is impractical , patients should wear long-sleeved shirts, trousers rather than shorts, and wide-brimmed hats and should use sunscreens. Many effective sunscreens are available commercially; however, none can completely obviate the potential for significant sun exposure to exacerbate SLE (see Appendix E).
   2. Situational stresses. Some patients may experience increased disease activity during periods of fatigue or emotional stress (e.g., when encountering school examinations or interpersonal conflict). The significance of such factors should not be overlooked, and such stress should be reduced as much as possible.
   3. Infection. Viral infection has been suggested as an etiologic event in SLE. Although unproven as such, viral infection may provoke a flare of disease by an unknown mechanism, perhaps involving superantigens. Concern that exposure to foreign antigen might be harmful has led to some reluctance to immunize patients with SLE. However, current studies with influenza and pneumococcal vaccines suggest that such vaccination provides protection without causing increased SLE disease activity. Specific antibody responses may be lower than those in normal subjects, especially in patients on immunosuppressive agents.
   4. Drugs. Many drugs have been associated with the development of ANAs and, in some cases, a clinical lupuslike syndrome (Table 30-2); procainamide and hydralazine are the most commonly implicated. However, the potential to induce such serologic changes in non-SLE patients does not preclude the use of these drugs in SLE patients. Although most physicians prefer to avoid them if an alternative drug is available, the use of these drugs in SLE has not been associated with documented exacerbation of disease activity.
      
      
      

      
      

      Table 30-2. Drugs implicated in drug-induced lupuslike syndrome

      
      
      

IV. Clinical presentation. SLE is a multisystem disease in which the diagnosis rests on the recognition of a constellation of clinical and laboratory findings. No single finding makes the diagnosis, although some findings, such as antibodies to double-stranded DNA or a characteristic malar rash, are more suggestive than others. As a result of the wide spectrum of manifestations and severity of disease, criteria for diagnosis have been devised to ensure at least minimum uniformity for disease classification in clinical studies (Table 30-3). The presence of four criteria (not necessarily occurring simultaneously ) is required to classify a patient as presenting with SLE.

Table 30-3. Revised American College of Rheumatology criteria for classification of systemic lupus erythematosus

1. Fever is a common manifestation of active SLE. Although often above 103F at times, sustained fever of such magnitude is not common and should stimulate a search for infection. Acute severe disease (lupus crisis) may be accompanied by fever up to 106F.
2. Skin. Facial erythema is more common than the classic butterfly eruption as an acute cutaneous manifestation; photosensitivity dermatitis and bullous lesions may also occur. Subacute cutaneous LE includes both annular and papulosquamous lesions. Chronic discoid lesions with central atrophy, depigmentation, and scarring or nonscarring alopecia are common occurrences in 20% to 30% of patients. Mucous membrane lesions with ulcers of the hard palate and nasal septal perforations may be present. Raynaud's phenomenon may be associated with acrosclerosis and, uncommonly, digital ulceration. Purpura and ecchymosis may occur as a result of either disease (e.g., thrombocytopenia) or corticosteroid treatment.
3. Musculoskeletal system
   1. Arthritis is common and affects both small and large joints in a symmetric pattern. The axial spine is not involved. Even in the face of long-standing arthritis, bony erosions are uncommon. Reducible joint deformity is caused by capsular laxity and both tendinous and ligamentous involvement, which lead to partial subluxation. Tendon ruptures may occur. Monarticular or asymmetric joint symptoms may also derive from osteonecrosis, most often in large, weight- bearing joints, or joint infection.
   2. Inflammatory myositis may occur in 5% to 10% of patients. Muscle weakness may also reflect corticosteroid-induced myopathy, rarely chloroquine-induced myopathy, or a myasthenia gravis-like syndrome associated with SLE.
4. Cardiovascular system. The major cardiovascular morbidity associated with SLE appears to be accelerated coronary artherosclerosis and ischemic coronary disease.
   1. Pericarditis is the most common cardiovascular manifestation. Pericardial effusions demonstrable by echocardiogram may be present in up to 60% of patients. Symptomatic pericarditis occurs in about 25% of patients. Tamponade is rare.
   2. Myocardial disease, evidenced by signs ranging from persistent tachycardia to frank myocardial infarction, may also occur. The basis is often unknown but may include primary muscle involvement. Atherosclerosis is the most common cause of coronary artery disease in SLE, but coronary vasculitis may occur. Determination of anti-cardiolipin antibodies may be useful in lupus patients with myocardial infarction.
   3. Verrucous endocarditis (Libman-Sacks endocarditis) is a pathologic diagnosis, as it rarely causes clinically significant valvular lesions or embolic complications. It most commonly affects the posterior leaflet of the mitral valve and may predispose the patient to bacterial endocarditis.
   4. Peripheral vascular manifestations include vasculitis that usually affects small arteries, arterioles, and capillaries, especially those of the skin. Phlebothrombosis and thrombophlebitis may occur and recur in some patients as a sign of disease activity and in relation to anti-cardiolipin antibodies. Gangrene is rare. Raynaud's phenomenon may be a feature in up to 25% of patients.
   5. Pulmonary hypertension may occur without relationship to overall disease activity. The clinical presentation is similar to that of idiopathic pulmonary hypertension, although with a higher incidence of Raynaud's phenomenon.
5. Pulmonary system
   1. Pleuritis is the most common pulmonary symptom. Pleural effusions may occur in up to 50% of patients and pleuritic pain in 60% to 70% of patients. Although it is impractical to analyze the pleural fluid of each patient during each occurrence, effusions may be secondary to processes other than active SLE or infection, and pulmonary emboli should always be considered in the differential diagnosis.
   2. Pneumonitis as evidenced by rales on physical examination and patchy infiltrates or platelike atelectasis on chest radiography is a diagnostic problem. Because SLE patients are often compromised hosts , infection by either common or uncommon agents must be considered. Lupus pneumonitis does occur, but this diagnosis requires exclusion of other processes. Progressive lupus pneumonitis ending in acute pulmonary insufficiency is uncommon. Lung biopsy may be required to establish a diagnosis, especially in the setting of persistent or progressive findings despite therapy. Abnormal findings on pulmonary function tests such as moderate restrictive and obstructive deficits are common, but patients usually have mild or no associated symptoms.
6. Gastrointestinal systems. Abdominal pain is a common complaint and may reflect gastrointestinal disorders associated with medications or intrinsic SLE-related pathology. Sterile peritonitis (serositis) and mesenteric vasculitis may be difficult to document. Intestinal perforation, especially in patients on corticosteroids that can mask symptoms, must be considered in addition to spontaneous bacterial peritonitis. Pancreatitis may also occur. Hepatomegaly may occur in one-fourth of patients, but abnormal liver function test findings are often drug- related rather than indicative of intrinsic lupus-associated liver damage. Chronic active hepatitis with positive tests for LE cells or ANAs (lupoid hepatitis) is not part of the spectrum of SLE. Splenomegaly may be found in the setting of active disease and splenic infarcts can occur.
7. Other systems. Lymphadenopathy is common but obviously not specific. Conjunctivitis, keratoconjunctivitis sicca, episcleritis, and retinal exudates (cytoid bodies) may be present. Parotid enlargement with or without a dry mouth (xerostomia) is reported in up to 8% of patients.

V. Laboratory abnormalities

1. Auto-antibodies to nuclear and cytoplasmic antigens occur in SLE. Their detection is diagnostically significant, although the sensitivity and specificity for SLE vary with each specific auto-antibody (Table 30-4). Because these auto-antibodies participate in immunologically mediated tissue damage, correlation between disease activity and antibody titer has been sought with the hope that antibody level (especially anti-DNA antibody level) might provide an index of disease activity and a guide to therapeutics. The utility of this approach, however, is problematic , as severe disease does not develop despite conservative treatment in some patients with persistently abnormal values. Indeed, there are some patients who have had only laboratory abnormalities with no symptoms for many years. The different technologies available for measuring any given auto-antibody do not necessarily provide comparable results. Although both IgM and IgG rheumatoid factors may occur in up to one-third of patients, their presence does not correlate with the presence of articular disease.
   
   
   

   
   

   Table 30-4. Auto-antibodies in systemic lupus erythematosus

   
   
   
2. Serum complement is often abnormally low in conjunction with elevated auto-antibody titers. Hypocomplementemia per se is not specific for SLE and may reflect any immunologically mediated disease accompanied by complement consumption, a hereditary complement component deficiency, impaired synthesis, or an improperly handled serum sample. In the context of SLE, hypocomplementemia is often, but not invariably, associated with nephritis. Like anti-DNA antibody levels, complement titers are valuable as a therapeutic guide in some but not all patients.
3. Routine laboratory examination may reveal abnormalities.
   1. Hematology
      1. Anemia occurs in more than 50% of patients, especially during active disease. Most anemias in SLE are of the chronic disease type (normochromic, normocytic with low serum iron and total iron binding capacity). Results of the direct Coombs' test may be positive in approximately 25% of patients; true hemolytic anemia occurs in 10% of patients. The Coombs' test result may represent cell surface immunoglobulin (IgG), complement (C3, C4), or both. Anemia from blood loss or microangiopathic hemolytic anemia must always be considered.
      2. Leukopenia. SLE patients are often leukopenic, especially during periods of disease activity. Lymphopenia caused by anti-lymphocyte antibodies is the most common type, but antibody-mediated neutropenia can occur. Anti-stem cell antibodies are rare.
      3. Thrombocytopenia. Anti- platelet antibodies have been demonstrated by a direct test similar to Coombs' test.
      4. Prolongation of the partial thromboplastin time. Antibodies to both individual components of the clotting cascade (VIII, IX, XII) and to the prothrombin-converting complex have been described. The lupus anticoagulant is not corrected by addition of normal plasma to the patient's plasma. In the presence of normal platelets, the lupus anticoagulant does not appear to cause clinically significant bleeding, but it does lead to an increased propensity to venous and arterial thrombosis.
      5. False-positive reaction to serologic test for syphilis. A small percentage of biologic false-positive reactions show a positive fluorescent treponemal antibody, which can be distinguished from a true positive by its beaded appearance. Circulating lupus anticoagulants and anti-cardiolipin antibodies are associated with a false-positive reaction to the serologic test for syphilis.
      6. The erythrocyte sedimentation rate is frequently elevated but is an inconsistent index of disease activity. It is not useful in differentiating active SLE from an intercurrent process, such as infection.
   2. Biochemistry. Apart from hypergammaglobulinemia, routine biochemical screening reflects the pattern and degree of organ involvement. Mild hyperkalemia in the absence of renal insufficiency may reflect an SLE-related renal tubular defect.

VI. Differential diagnosis. The diagnostic strategy for SLE involves recognition of a multisystem disease, the presence of certain serologic findings, and the absence of any other recognized disease process to explain the findings. Not all clinical and laboratory findings are of equal specificity; acute pericarditis and psychosis, as well as proteinuria and leukopenia, can have many causes other than SLE. Conversely, a discoid lupus rash and high titers of anti-native DNA antibodies or anti-Smith antigen antibodies strongly support the diagnosis. The art of diagnosis rests in recognizing a constellation of findings and giving each the appropriate clinical weight. Because the presentations of SLE are many and varied, the full differential diagnosis includes most of internal medicine.

1. The most common presentation is a young woman with polyarthritis; however, SLE is not the most likely cause of her symptoms. Rheumatoid arthritis or an infectious arthritis, such as gonococcal arthritis, must be considered first, as specific or curative therapy is available. Early in the course of uncomplicated lupus polyarthritis, radiographs of the joints are usually not helpful. The single most useful laboratory test to evaluate the possibility of SLE is the ANA determination. Although not completely specific, it is highly sensitive (Table 30-5). A positive test result is a signal to consider the diagnosis further, and a negative test result in a patient not receiving corticosteroid therapy makes the diagnosis unlikely .
   
   
   

   
   

   Table 30-5. Differential diagnosis of common serologic tests

   
   
   
2. Organ systems that may be affected by SLE include skin and mucous membranes (rash, ulceration, alopecia), joints (nondeforming, often symmetric polyarthritis and periarthritis), kidneys (glomerulonephritis), serosal membranes (pleuritis, pericarditis, abdominal serositis), blood (hemolytic anemia, leukopenia, thrombocytopenia), lungs (transient infiltrates, rarely progressive hemorrhagic pneumonitis), and nervous system (seizures, strokes, psychosis, peripheral neuropathies).
3. Other rheumatic diseases. Patients with multisystem disease and ANAs may have a condition other than SLE. Up to 40% of patients with rheumatoid arthritis may have ANAs. Systemic sclerosis (scleroderma), mixed connective tissue disease, and chronic active hepatitis must also be considered.
4. Drug-induced systemic lupus erythematosus-like syndrome. See Table 30-2 and Table 30-5.

VII. Treatment. The diagnosis of SLE does not mandate the use of corticosteroids. Treatment must be individualized. The therapeutic strategy must consider both the pattern and the severity of organ system involvement. The poor prognosis reported in earlier series has been altered because of an overall improvement in general medical care, an enlightened and balanced use of medications, and the capability to diagnose milder forms of the disease. General measures include adequate rest and avoidance of stress. Descriptions of specific measures follow.

1. Fever. Nonsteroidal antiinflammatory drugs (NSAIDs) (e.g., 600 to 900 mg of aspirin four times daily, 25 to 50 mg of indomethacin three times daily) and acetaminophen are effective antipyretics. Corticosteroids are not indicated for fever alone. Persistent or high fevers should always stimulate a search for infection, particularly in patients on steroids or immunosuppressive agents.
2. Skin rash. Avoidance of exposure to ultraviolet light to prevent exacerbation of both cutaneous and systemic disease is paramount. Sunscreens, wide-brimmed hats, long sleeves, and long pants should be used by all patients. Highly protective sunscreens should be applied liberally 1 to 2 hours before exposure and reapplied after any swimming or sweating.
   1. Topical therapy. Active skin disease should be treated with topical corticosteroid preparations (e.g., hydrocortisone, triamcinolone, or fluocinonide two to three times daily; see Appendix E) rather than with systemic corticosteroids. Occlusive dressings with cellophane wrap may be used at night, particularly on the upper extremities.
   2. Systemic therapy. The antimalarial hydroxychloroquine (200 mg PO twice daily) is used to supplement topical treatment of extensive lesions. Quinacrine (100 mg daily) is also effective. Regular ophthalmologic examinations at 6-month intervals should include a slit-lamp examination and measures of light and color perception thresholds. The drug should be tapered as soon as disease control permits . Systemic corticosteroids are usually not indicated for skin disease alone.
3. Arthritis
   1. Nonsteroidal antiinflammatory drugs (see Appendix E). Gastrointestinal intolerance and the presence of renal disease may limit therapy with NSAIDs in some patients. Occasionally, large elevations of liver enzymes may occur and require either reduction or termination of therapy. Transient changes in renal function with any NSAID may occur. The experience with NSAIDs other than aspirin includes several apparently idiosyncratic reactions in SLE patients manifested by fever and aseptic meningitis.
   2. Antimalarial drugs, including both hydroxychloroquine and quinacrine, may be effective in the treatment of joint pain and inflammation , fatigue, and skin rash. These drugs can also be used as steroid- sparing agents.
   3. Systemic corticosteroid. Oral prednisone (10 to 20 mg daily) is reserved for patients with accompanying constitutional symptoms unresponsive to NSAIDs.
   4. Methotrexate is a reasonable alternative to antimalarial agents or low-dose glucocorticoids in patients with persistent arthritis, rash, or serositis. Dose reductions are necessary for patients with renal insufficiency.
4. Serositis can be treated with an NSAID as outlined for arthritis. At times, severe pericarditis may require a short course of steroids. Rarely, a large pericardial effusion necessitates therapy with high-dose prednisone (20 mg three times daily). Adverse effects of long- term high-dose corticosteroid therapy are discussed under renal disease (see section VII.I.1 ).
5. Pneumonitis. Transient pulmonary infiltrates that clear spontaneously without therapy may occur. The major significance of the radiologic findings relates to differential diagnosis rather than therapeutics. Infection with routine or opportunistic pathogens must be considered. Infiltrates secondary to SLE may require therapy, especially if they are associated with other signs of disease activity. Fulminant pneumonitis with hemorrhage, which is rare, requires aggressive therapy with high-dose corticosteroids (20 mg of prednisone three times daily) and often cytotoxic agents (1 to 3 mg of azathioprine per kilogram daily, or 1 to 2 mg of cyclophosphamide per kilogram daily).
6. Hematologic abnormalities
   1. Hemolytic anemia is uncommon but may be severe and require corticosteroid therapy if symptomatic. Young patients can tolerate hemoglobin levels of 7 to 8 g/dL. When required, 40 to 60 mg of prednisone is given daily in two to three divided doses and tapered as quickly as possible with the hemoglobin and reticulocyte count used as guides. Microangiopathic hemolytic anemia (elevated lactate dehydrogenase, schistocytes) may be associated with SLE vasculitis and is often treated with high-dose steroids.
   2. Immune thrombocytopenia secondary to SLE usually responds to corticosteroid therapy. Platelet counts of 80,000 to 100,000 are considered adequate. Life- threatening thrombocytopenia unresponsive to several weeks of 60 mg of prednisone daily may improve with gamma globulin therapy (400 mg/kg IV daily for 5 days consecutively), which usually leads to an immediate (2 to 3 days) rise in the platelet count. Danazol, azathioprine, vincristine, vinca alkaloid-loaded platelets, and IV pulse cyclophosphamide have been used on occasions for steroid-resistant thrombocytopenia.
   3. Leukopenia in SLE usually represents lymphopenia rather than neutropenia and is not associated with the serious risk for infection that accompanies the leukopenia of cancer chemotherapy. Leukopenia usually does not warrant specific treatment per se, but it does improve when steroids are used to treat other disease manifestations.
7. Vasculitis. Small-vessel cutaneous vasculitis, usually found on the digits and palm of the hand, may be managed with low-dose prednisone (20 mg/d). Medium-vessel and large-vessel vasculitis, although uncommon, requires 60 mg/d in divided doses.
8. Neurologic disease
   1. Seizures require the use of anticonvulsant drugs. Initial therapy is 300 to 400 mg of phenytoin daily, with monitoring of serum drug levels. If needed to achieve seizure control, 20 to 60 mg of phenobarbital three times daily is added.
   2. Psychosis may be secondary to either steroid therapy or SLE.
      1. Steroid-induced psychosis will improve with tapering of systemic corticosteroids. Major tranquilizers, such as 1 mg of haloperidol twice daily, initially will assist in control of psychotic manifestations.
      2. Systemic lupus erythematosus-related psychosis. The occurrence of SLE-related psychosis does not necessarily require an increase in steroid therapy. If adequate behavioral control is achieved with major tranquilizers and no organic signs are present on either physical examination or cerebrospinal fluid analysis, corticosteroids are not initiated or increased.
   3. Parenchymal central nervous system disease. In the presence of new focal neurologic findings, 20 mg of prednisone is given three times daily until either improvement or toxicity is observed . Some neurologic lesions are not responsive to steroids. If no improvement is evident after about 3 to 4 weeks of high-dose therapy, prednisone is tapered to avoid complications. Dosages of prednisone above 60 to 80 mg daily rarely produce additional therapeutic benefit but markedly increase the risk for serious side effects. Any trial of very high-dose prednisone in severe disease should continue only for a predetermined, limited period of time. Pulse methylprednisolone therapy may be helpful for patients who do not respond to standard therapy. Cytotoxic agents such as IV cyclophosphamide have been used in steroid-unresponsive SLE patients with severe central nervous system disease.
   4. Peripheral nerve disease. Peripheral neuropathy is common. Mononeuritis multiplex usually represents small-vessel vasculitis. If the patient is unresponsive to 60 mg of prednisone daily in three divided doses, then 1 to 3 mg of azathioprine per kilogram or 1 to 2 mg of cyclophosphamide per kilogram may be initiated.
9. Renal disease. For the initial management of active renal disease, as defined by active urinary sediment including red blood cells and red cell casts, proteinuria, and a decrease in creatinine clearance, the intensity of therapy is often defined by the severity of presentation and extra-renal manifestations of disease. Response to a chosen treatment is assessed by serial urinalyses, 24- hour urine testing, and determination of levels of serum complement and anti-DNA antibodies. Although renal biopsy is helpful in characterizing the type of renal lesion and extent of acute and chronic change, it is not mandatory. Patients with diffuse proliferative or membranoproliferative glomerulonephritis have the worst prognosis, but the natural history of clinically silent, diffuse proliferative disease with normal renal function has not been determined. Chronic changes of fibrosis and atrophy suggest little reversible disease and a poor prognosis. Any therapeutic regimen must consider both short-term and long-term effects encountered during the management of chronic nephritis.

   Infection and drug-related causes of renal abnormalities must be sought and corrected. Vigorous control of blood pressure and avoidance of nephrotoxins is mandatory.

   1. Corticosteroid therapy is the mainstay of treatment for active nephritis. The dosage, route of administration, and duration of therapy vary depending on the initial presentation, presence of comorbidities, and prior treatment modalities. Two approaches have been employed for the management of active nephritis.

      Prednisone (60 mg daily in divided doses) for 1 to 2 months: Resolution of signs of active disease commonly permits tapering of prednisone. A recurrence of active urinary sediment, increased proteinuria, and decreased kidney function may prompt an increase in steroid dosage, a switch to pulse steroids, or a decision to perform a kidney biopsy in preparation for consideration of cyclophosphamide therapy.

      High-dose, pulse methylprednisolone: This regimen is defined by courses of 1,000 mg/d for 3 days monthly for 6 months, with 0.5 mg of oral prednisone per kilogram between pulses , to control both renal and extra-renal manifestations. It is used as (a) initial therapy for active nephritis, (b) sole therapy to avoid cumulative side effects of long-term daily steroids, or (c) therapy for exacerbations of severe disease that do not respond to daily oral steroids.

      Although prednisone clearly helps to relieve acute exacerbations of disease, long-term corticosteroid therapy is associated with serious side effects.

      1. Physical appearance is altered by weight gain that produces truncal fat deposition (moon facies, buffalo hump), hirsutism, acne, easy bruising, and purple striae. Although individual patients differ in their susceptibility to these changes, reduction of the steroid dosage will eventually reduce the severity of these manifestations.
      2. Infection occurs with greater frequency in corticosteroid-treated patients. Corticosteroids may mask both local and systemic signs of infection. Minor infections have a greater potential to become systemic. Latent infections, especially mycobacterial varieties, may become activated, and opportunistic agents such as fungi, Nocardia, and Pneumocystis carinii may cause serious clinical problems. Skin testing for delayed hypersensitivity to Mycobacterium tuberculosis should be performed before the initiation of corticosteroid therapy. However, a negative reaction may reflect the altered immunity of active SLE rather than lack of previous exposure to M. tuberculosis.
      3. Mental function may be altered. Minor reactions include irritability, insomnia, euphoria, and inability to concentrate. Major reactions may include severe depression, mania, and paranoid psychoses.
      4. Glucose intolerance may be induced or exacerbated by corticosteroids. Insulin may be required to control hyperglycemia and should be adjusted as the corticosteroid dosage is changed.
      5. Hypokalemia may be caused by preparations with mineralocorticoid activity. Serum potassium should be checked frequently, especially if congestive heart failure, nephrosis, or peripheral edema producing secondary hyperaldosteronism is present.
      6. Sodium retention, edema, and hypertension may be induced by all corticosteroid drugs. When these effects become clinically significant, agents with fewer salt-retaining properties can be used. Alternative steroid preparations are listed in Appendix E. Because steroids should be given only for major SLE manifestations, it is usually not feasible to control hypertension by a reduction in dosage; therefore, blood pressure must be controlled by appropriate antihypertensive therapy.
      7. Myopathy may occur in patients receiving long-term, high-dose steroids. The muscles are not tender, and unlike inflammatory myositis, steroid-induced myopathy is usually not characterized by elevated serum muscle enzymes. Proximal weakness is the most common symptom. Weakness of the pelvic girdle is more common than shoulder-girdle symptoms. Biopsy may be useful in distinguishing inflammatory, SLE-related myositis from non-inflammatory, corticosteroid-induced myopathy. Drug-induced myopathy will gradually improve with a reduction of corticosteroid dosage.
      8. Skeletal abnormalities include osteopenia and osteonecrosis. Corticosteroids may reduce gastrointestinal calcium absorption , induce secondary hyperparathyroidism, and also reduce collagen matrix synthesis by osteoblasts. Compression fractures in the vertebral spine represent a major secondary complication, especially in older patients. They occur in about 15% of steroid-treated patients. Prophylactic vitamin D ₃ (400 U twice daily) and calcium (1,500 mg/d from dietary and supplemental sources) are recommended. Patients receiving long-term corticosteroid therapy (for more than 1 month) should undergo baseline and yearly bone density evaluations and treatment with suitable bisphosphonates if necessary (see Chapter 46). Osteonecrosis occurs most frequently in weight-bearing joints, especially the femoral heads. The mechanism is unknown (therapy is discussed in Chapter 45). Reduction in corticosteroid dosage is desirable whenever possible, although it is unlikely to affect established osteonecrosis.
      9. Hypoadrenalism may occur during periods of physiologic stress in patients with suppression of the hypothalamic- pituitary - adrenal axis resulting from exogenous steroid administration. During episodes of surgery or major intercurrent illness, it is advisable to provide supplemental steroid therapy to patients who are receiving corticosteroid therapy or who have discontinued such therapy within the previous year. Hydrocortisone (300 mg/d or equivalent dosage in three divided doses) may be given IV or IM during the period of maximum stress and subsequently tapered during 5 days. The stress of major nonsurgical illness may be managed with an increase in daily steroid dosage to at least the equivalent of 30 mg of prednisone.
      10. Other side effects of corticosteroids include increased intraocular pressure, which may precipitate glaucoma, and the occurrence of posterior subcapsular cataracts. Although dyspepsia may accompany the use of steroids, it usually responds to antacids or histamine ₂ blockers and administration of medication with meals. Enhancement of peptic ulcer disease probably does not occur. Menstrual irregularities, night sweats, and pancreatitis have been associated with corticosteroid therapy. Pseudotumor cerebri, associated with rapid steroid dosage reduction, is a rare complication.
   2. Cytotoxic drugs are used in either severe corticosteroid-resistant disease or in the context of unacceptable steroid side effects. In patients with diffuse proliferative glomerulonephritis, cyclophosphamide has shown to retard progression of scarring in the kidney and reduce the risk for end-stage renal failure. Monthly infusions of IV pulse cyclophosphamide (0.5 to 1.0 g/m ² of body surface area) preserve renal function more effectively than do corticosteroids alone, but the rate of relapse following a 6-month course is high. Most patients require extended therapy. Potential toxicities are substantial: nausea and vomiting (often requiring treatment with antiemetic drugs); alopecia (reversible); ovarian failure (nearly universal in patients more than 30 years old) or azoospermia; and hemorrhagic cystitis, bladder fibrosis, and bladder transitional cell or squamous carcinoma. Intermittent IV cyclophosphamide may decrease the incidence of bladder complications associated with daily oral therapy. Azathioprine (1 to 3 mg/kg daily) is a far less toxic drug that avoids the potential complications of alopecia, sterility, and hemorrhagic cystitis associated with cyclophosphamide, but it is considered less effective. Each agent requires careful monitoring of complete blood cell counts. Allopurinol should not be used with azathioprine because it inhibits azathioprine catabolism. The long-term toxicity of these agents may include both hematopoietic malignancy and solid tumors (lymphomas with azathioprine, bladder carcinoma with cyclophosphamide).
   3. Other regimens. Controlled trials of plasmapheresis have not shown benefit in most cases. Currently, clinical experience is being gathered with methotrexate and mycophenolate mofetil, but no controlled studies are available. Clinical experience with cyclosporin A (3 to 6 mg/kg daily) suggests that it might be useful in membranous glomerulonephritis. Side effects, particularly hypertension and renal toxicity, appear to be infrequent.
10. Special management considerations
    1. Idiopathic drug reactions. The possibility of an increase in allergic drug reactions in SLE patients is controversial . However, some observations suggest that sulfonamide and quinolone drugs may exacerbate SLE. Fever and meningeal irritation have been reported in SLE patients taking ibuprofen, sulindac, and tolmetin.
    2. Drug-induced lupus. Medications associated with drug-induced lupus (see Table 30-2) have been used extensively and effectively in patients with idiopathic SLE. Although the risk for exacerbating the underlying disease is often discussed, such risk has not been established and does not contraindicate the use of an otherwise indicated medication.
    3. Pregnancy . The effects of pregnancy on SLE are variable and are discussed in detail in Chapter 24.
    4. Contraception. Because SLE is a disease of women of childbearing age, contraception is an important issue. Barrier protection condoms and a diaphragm are preferable because they have no adverse effects. However, the patient's willingness to use these methods effectively must be considered. Because hormonal manipulation might theoretically exacerbate SLE, oral contraceptives with progesterone only or with a combination containing the lowest estrogen dose are preferable.
    5. Hormone replacement. The effects of estrogen replacement therapy on SLE disease activity remain unclear. Although it may prove useful as a means to reduce the risk for osteoporosis and atherosclerosis in women with SLE, estrogen replacement therapy in SLE patients is controversial and is the subject of a national collaborative study. It is clearly contraindicated in those with a history of thrombosis or anti-phospholipid antibodies.
    6. Hemodialysis. SLE patients appear to tolerate long-term hemodialysis as well as any population with chronic renal failure. Clinical impressions suggest that SLE patients may have more quiescent disease once on dialysis, but they may still occasionally experience SLE disease activity.
    7. Transplantation . SLE patients may undergo renal transplantation without any apparent increase in morbidity in comparison with other transplantation populations. Recurrences of lupus in transplanted allografts are rare.

VIII. Prognosis. The prognosis of SLE has improved, largely because milder forms of disease have been recognized, but also through the availability of potent antibiotics, the development of intensive care units, and probably the use of corticosteroids and immunosuppressive agents in the more severely ill patients. Prognosis depends on the pattern of organ involvement; patients with renal and central nervous system disease have the worst 5-year survival rates. Infection continues to be a major cause of death. Recent series show 5-year survival rates of about 90%.

1. Drug-induced lupus. Many drugs (see Table 30-2) have been implicated in the induction of a lupuslike syndrome, with manifestations ranging from an isolated positive ANA test result to a clinical lupus syndrome. Procainamide and hydralazine are the drugs most frequently reported to produce a lupuslike syndrome.
   1. Clinical features. Skin rash, arthritis, pleural and pericardial effusions, lymphadenopathy, splenomegaly, anemia, leukopenia, elevated erythrocyte sedimentation rate, and transient false-positive serologic tests for syphilis may all be included. Pleuropulmonary disease is prominent, and renal and central nervous system disease are characteristically absent. Most manifestations resolve after discontinuation of the drug.
   2. Laboratory studies. The laboratory profile of a patient with drug-induced lupus may help distinguish the syndrome from spontaneous SLE. Serum complement is rarely reduced in the drug-induced syndrome, and antibodies to native (or double-stranded) DNA are usually absent. However, antibodies to single-stranded DNA are often present, in addition to antibodies to histones and ribonucleoproteins.
   3. Treatment of drug-induced lupus involves discontinuation of the offending agent and symptomatic management of the clinical manifestations. Because most manifestations are reversible, therapy is usually of short duration. A positive ANA test result alone should prompt review of the indications for use of the inciting agent but does not per se require the addition of therapeutic agents.
2. Discoid lupus erythematosus
   1. Clinical presentation. Disease may be limited to the skin and assume the chronic discoid form, with scaling red plaques and follicular plugging. Healing of these lesions is associated with central scarring and atrophy. Although chronic discoid lupus erythematosus remains primarily cutaneous in the majority of patients, SLE will develop in a small percentage (about 5%). Conversely, patients with SLE may have discoid lesions among the cutaneous manifestations of their disease. Certain types of skin lesions, such as those of subacute cutaneous lupus erythematosus, may reflect a specific immunogenetic predisposition.
   2. Therapy follows the same principles as those outlined for skin disease in SLE: avoidance of sun and ultraviolet exposure and use of topical steroids and hydroxychloroquine (see Chapter 11 for more information regarding discoid lupus erythematosus).

Bibliography

Boumpas DT, et al. Systemic lupus erythematosus: emerging concepts. Part 1. Ann Intern Med 1995;122:190.

Boumpas DT, et al. Systemic lupus erythematosus: emerging concepts. Part 2. Ann Intern Med 1995;123:42.

Klippel JH, Dieppe PA, eds. Rheumatology, 2nd ed. London: Gower Medical Publishing, 1997.

Lahita RG, ed. Systemic lupus erythematosus. New York: Churchill Livingstone, 1992.

Ropes MW. Systemic lupus erythematosus. Cambridge, MA: Harvard University Press, 1976.

Wallace DJ, Hahn BH, eds. Dubois' lupus erythematosus, 5th ed. Baltimore: Williams & Wilkins, 1997.

Books@Ovid
Copyright 2000 by Lippincott Williams & Wilkins
Stephen A. Paget, M.D., Allan Gibofsky, M.D., J.D. and John F. Beary, III, M.D.
Manual of Rheumatology and Outpatient Orthopedic Disorders