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1、Ch叩ter 289 SYSTEMIC LUPUS ERYTHEMATOSUSPeter H. SchurSystemic lupus erythematosus (SLE) is a disease of unknown cause that may produce variable combinations of fever, rashz hair loss, arthritis, pleuritis, pericarditis, nephritis, anemia, leukopenia, thrombocytopenia, and central nervous system (CNS
2、) disease. The clinical course is characterized by periods of remissions and acute or chronic relapses. Characteristic immune abnormalities, especially antibodies to a number of nuclear and other cellular antigens, develop in patients with SLE. The diagnosis is facilitated by determining whether the
3、 patient has 4 of the 11 clinical and/or laboratory criteria developed for the classification of SLE(Table 289-1).EPIDEMIOLOGY.SLE can occur at any age but has its onset primarily between ages 16 and 55. It occurs more frequently in women. In children, the female-male ratio is 1.4 to 5.8:1; in adult
4、s, it ranges from 8:1 to 13:1; and in older individuals, the ratio is 2:1. The prevalence of SLE is estimated to be between 4 and 250 cases per 100,000 population. In thellnited States, the highest incidence is among Asians inHawaii,Thus emotional support is essential, as well as counseling and the
5、provision of written (and other) material. Patients should be assured that SLE is mild in most patients, that it is rarely life threatening, and that serious organ involvement can usually be prevented. Support by family, friends, and organizations such as the Lupus Foundation of America and the Arth
6、ritis Foundation is often helpful.It is important to determine whether the symptoms and signs are due to SLE or something else(Table 289-10). For instance, fever is more likely to be due to an infection and fatigue due to lack of sleep. Low complement levels, high anti-DNA levels, and/or high immune
7、 complex levels suggest active SLE.Preventive measures are useful. Patients should avoid using sulfonamides, penicillin, and high-estrogen birth control pills, which may exacerbate the lupus. Exercise has been demonstrated to ameliorate the fatigue associated with SLE. Patients should be questioned
8、regarding their degree of photosensitivity; not all patients have photosensitivity, and the degree may vary, including variation over time. Photosensitive patients should use sunscreens daily with an SPF of at least 15; for those who are very photosensitive, sunscreen should be used twice daily.Phot
9、osensitizing medications (e.g.z tetracyclines, psoralens) should be avoided. In postmenopausal women, estrogen is recommended for its benefit regarding osteoporosis and coronary artery disease (women with SLE are at excess risk for these conditions), unless the patient has contraindications or the S
10、LE relapses. Immunization with flu and pneumococcal vaccines is advisable.In treating SLE one should consider which organ is involved and to what degree (nseverity).Table 289-llprovides an outline of therapy based on organ involvement; treatment starts conservatively and, if the response is inadequa
11、te, becomes more aggressive.Treatment of lupus nephritis(Table 289-12)should be based on whether the disease is considered active, the type of nephritis (see earlier), and the severity. The goal of treatment should be to improve, maintain, and prevent deterioration in renal function. For mesangial o
12、r focal glomerulonephritis, bed rest or a short course of prednisone (30 mg/day) will usually suffice to clear the urinary and serologic abnormalities. For diffuse proliferative glomerulonephritis, more vigorous treatment is usually given. Patients are generally treated with 1 mg/kg of prednisone. I
13、f azotemia is present (especially if the creatinine level is greater than 1.2 mg/dL), an immunosuppressive should be added, either azathioprine in doses of 50 to 200 mg/day (a dose to achieve slight leukopenia) or cyclophosphamide. Pulse steroids (1 g of IV methylprednisolone per day for 1 to 3 dose
14、s) may be useful acutely until the immunosuppressives start working (which may be 7 to 10 days). Cyclophosphamide given intravenously (in the morning) once monthly (for 6 months) and then every 3 months (for eight doses) appears to be as effective, and less toxic than the same drug given by mouth. T
15、he risks of this therapy (malignancy, infections, hair loss, infertility) should be discussed with patients. The initial dose is 0.85 g/1.7 m2body surface area. The WBC count is determined 7 to 10 days later, and the next dose is adjusted (to a maximum of 2 g/1.7 m2) to achievea WBC count of about 4
16、000. Acute membranous glomerulonephritis usually responds to high closes of prednisone (1 mg/kg of prednisone per day) or pulse steroids. If not, a trial of immunosuppressives should be instituted. Hypertension should be treated vigorously; angiotensin-converting enzyme inhibitors appear to help pro
17、teinuria. Diuretics are useful to control edema and hypertension. There is no evidence that plasmapheresis benefits the management of lupus nephritis. For active renal disease, patients should be monitored once a week with urinalysis, serum creatinine determination, and immune function tests (comple
18、ment, anti-DNA). When the disease becomes inactive, monitoring will be less frequent, depending on the degree of residual damage-patients with nephrotic-range proteinuria or those with azotemia need to be monitored more closely.Acute neuropsychiatric lupus should be treated aggressively and quickly
19、in the hope of reversing the process, which usually means high doses of prednisone (1 to 2 mg/kg), as well as antipsychotics. Once the psychosis has cleared, the dosage of steroids should be tapered rapidly because patients are at high risk for infection; adding immunosuppressives, particularly cycl
20、ophosphamide, may be beneficial. Steroids themselves may induce psychosis; therefore it is important to serially monitor the patient with objective measures, including EEGZ MRI, and some antibrain antibodies, as well as CSF protein. However, often one must rely on clinical judgment. Seizure disorder
21、s are treated with anticonvulsants (e.g.z phenytoin, phenobarbital, carbamazepine); no evidence exists that these medications exacerbate SLE. Multiple small strokes may be due to antiphospholipid antibodies.Treatment of the antiphospholipid antibody syndrome remains controversial. Low levels of this
22、 antibody rarely cause symptoms. Patients with high levels and no symptoms should be treated with low-dose aspirin (81 mg/day); with symptoms, chronic warfarin (Coumadin) therapy is used at a dosage to maintain an International Normalized Ratio between 3 and 4.Patients started on prednisone therapy
23、should receive high doses only until the inflammation has subsidedthus the patient should be assessed frequently regarding specific organ function, as well as immune status (complement, anti-DNA antibodies). For acute, severe lupus, split doses are recommended, then a switch to a daily morning dose.
24、 For long-term management, the benefit-risk issue needs to be discussed. The prednisone dosage should then be tapered, the rate depending on the severity of organ inflammation and damage, the maximum dose, and side effects from prednisone (i.e., psychological changes, insomnia, weight gain, hyperten
25、sion, diabetes, peptic ulcer, infections such as acne, Cushingoid features, adrenalPROGNOSIS.The prognosis for SLE patients in theUnited Stateshas improved dramatically since the 1950s, when the survival rate was approximately 50% at 5 years; in 1994, it was approximately 90% at 10 years. The progno
26、sis is worse for those with CNS involvement, hypertension, azotemia, and early age of onset. The major cause of death is infection. Although there is an impression of greater awareness of the disease, its clinical expression has not changed in 20 years; nor is there evidencethat it is being diagnose
27、d earlier.ReferenceCervera R, Khamashta MA, Font Jz et al: Systemic lupus erythematosus: Clinical and immunologic patterns of disease expression in a cohort of 1000 patients. Medicine (Baltimore) 72:113, 1993. The largest cohort described in a cooperative European anthology- - percentage of clinical
28、 and immunologic features.Hahn B, Wallace D (eds): Dubois Lupus Erythematosus.Malvern,PA, Lea & Febiger, 1993./excellent source.Lahita RG (ed): Systemic Lupus Erythematosus.New York, Churchill Livingstone, 1992./ comprehensive series of chapters on both mechanism and treatment arranged by organ syst
29、ems.Schur PH (ed): The Clinical Management of Systemic Lupus Erythematosus, 2nd ed.Philadelphia, JB Lippincott, 1996./ book for internists and generalists on practical management ofSLEpatients.blacks, and certain Native Americans (Sioux, Crow, Arapahoe). The risk of SLE developing in a black America
30、n female has been estimated to be 1:250. The prevalence is about the same worldwide; the disease appears to be common inChina, in Southeast Asia, and among blacks in the Caribbean, but is seen infrequently in blacks inAfrica. Limited observations suggest that the incidence of discoid lupus erythemat
31、osus is the same as that for SLE.ETIOLOGY.The cause of SLE remains unknown, although many observations suggest a role for genetic, hormonal, immune, and environmental factors. The evidence for a genetic role is summarized inTable 289-2. Some of these genetic marker associations are found more freque
32、ntly in SLE patients of different races and ethnicities. It has been calculated that at least four genes are involved in predisposing individuals to SLE. Each gene presumably affects some aspect of immune regulation, protein degradation, peptide transport across cell membranes, immune response, comp
33、lement, the reticuloendothelial system (including phagocytosis), immunoglobulins, apoptosis, and sex hormones. Thus combinations of dissimilar gene defects may result in distinct abnormal responses and produce separate pathologic processes and different clinical expression.The evidence for hormonal
34、abnormalities is based primarily on the observation that SLE is much more common among women in their childbearing years. In addition, SLE has been observed in some males with Klinefelters syndrome, and some abnormalities of estrogen metabolism have been noted inboth men and women with SLE. However,
35、 the clinical expression of SLE is the same in men and women. Furthermore, a lupus-like disease of New Zealandmice is more common and more severe and has an earlier onset in females-and is ameliorated by oophorectomy or treatment with male hormones. Howevei; in other strains of mice with a lupus-lik
36、e disease, this gender difference is not noted.Numerous immune abnormalities occur in patients with SLE, the etiology of which remains unclear; nor do we know which are primary and which are secondary. Some of these immune defects are episodic, and some correlate with disease activity. SLE is primar
37、ilyPATHOGENESIS.Many manifestations are mediated by antibodies. The classic example is that of diffuse proliferative glomerulonephritis. Immune complexes, which consist of nuclear antigens (especially DNA) and high-affinity complement-fixing IgG (especially IgGl and IgG3) and ANAs (especially antibo
38、dies to DNA), form in the circulation and are deposited in the glomerular basement membrane (GBM) or form in situ; histone may facilitate immune complex deposition. The complement system is then activated and chemotactic factors are generated. These factors induce the attraction and infiltration of
39、leukocytes, which then phagocytose immune complexes and cause the release of mediators (such as activators of the clotting system), which further perpetuate the glomerular inflammation. With continuing immune complex deposition, chronic inflammation may ensue, ultimately leading to fibrinoid necrosi
40、s and scarring (crescents) and loss of renalfunction. In lupus membranous glomerulonephritis, similar mechanisms occur, although immune complex-containing, poorly complement-fixing IgG2 and IgG4 form primarily in situ on the GBM; there is no cellular infiltrate. The mechanism for the GBM protein lea
41、kage, which results in the nephrotic syndrome, is not clear. In lupus mesangial glomerulonephritis, mesangial cells (macrophage-likePATHOLOGY.Few unique pathologic features are associated with SLE. In patients with arthritis, the synovial histopathology tends to be non-specific, with superficial fib
42、rin-like material and local or diffuse cell lining proliferation. Vascular changes include perivascular mononuclear cells, lumen obliteration, enlarged endothelial cells, and thrombi, but fibrinoid necrosis is uncommon. Biopsies of the malar erythema may reveal some minor basal layer abnormalities,
43、as well as immune complex deposits at the dermal-epidermal junction. Discoid skin lesions are characterized by hyperkeratosis, follicular plugging, and more basal cell layer changes, including immune complexes at the dermal-epidermal junction. Pleura and pericardium are infiltrated by mononuclear ce
44、lls. Lupus pneumonitis is characterized by alveolar wall injury, hemorrhage, and edema; hyaline membrane formation; and immune complex deposits. Coronary arteries often demonstrate premature-onset atherosclerosis. Libman-Sacks endocarditis is characterized by the accumulation of immune complexes, mo
45、nonuclear cells, hematoxylin bodies, and fibrin and platelet thrombi. Pathologic examination of the spleen often reveals an onion skin appearance of the splenic arteries, which is thought to represent healed arteritis.RENAL DISEASE.Minimal disease (type IIA mesangial disease) of glomeruli has immune
46、 complex deposits only in mesangial cells. Type lib mesangial nephritis also has mesangial hypercellularity. Focal proliferative nephritis (type III) has segmental proliferation in glomerular tufts and in the mesangium and immune complex deposits in the mesangium and scattered granular deposits in t
47、he subendothelial, subepithelial, and intrabasement GBM. Active diffuse proliferative glomerulonephritis (type IV) affects more than 50% of glomeruli with cellular proliferation, necrosis, wire loops, subendothelial deposits, and hematoxylin bodies. When chronic, the process involves sclerosis, adhe
48、sions, crescents, and (tubular) atrophy. Extensive lumpy and bumpy deposits of immune complexes are present. In membranous nephritis (type V) diffuse, uniform thickening of the GBM is seen, with a fine granular deposition of immune complexes in the subendothelial region beneath fused foot processes.
49、 Tubular degenerative changes with interstitial mononuclear cells are not uncommon. Extensive crescent formation, representing scarring, indicates a poor prognosis.The brain is notable for the paucity of pathologic changes. Some minor blood vessel abnormalities, an occasional microinfarct, and some perivascular infiltration have been noted.CLINICAL MANIFESTATIONS.SLE is highly variable in onset as well as course. The initial symptoms may be non-specific(Table 289-4)and include myalgia, nausea, vomiting, head