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An inflammatory connective tissue disorder of unknown etiology occurring predominantly in young women, but also in children; 90% of cases occur in women. The sera of most patients contain antinuclear antibodies, including anti-DNA antibodies.
Pathology, Symptoms, and Signs
Clinical findings vary with the acuteness of the disease and the distribution of the lesions. SLE may begin abruptly with fever, simulating acute infection, or may develop insidiously over months or years with episodes of fever and malaise. Manifestations referable to any organ system may appear. As many as 90% of patients complain of articular symptoms, ranging from intermittent arthralgias to acute polyarthritis, some for years before other manifestations appear. A past history of "growing pains" in childhood is not uncommon. In long-standing disease, tendon contractures and secondary joint deformity may occur without x-ray evidence of erosion (Jaccoud's arthritis).
A characteristic malar "butterfly" erythema is one of several cutaneous lesions that may occur; others include the discoid lesions described above under DLE, and erythematous, firm, maculopapular lesions of the face, exposed areas of the neck, upper chest, and elbows. Blistering and ulceration are rare, though ulcers on mucous membranes (particularly the central portion of the hard palate near the junction of the hard and soft palate, the buccal and gum mucosa, and the anterior nasal septum) are common. Generalized alopecia is frequent during active phases of the disease. Mottled erythema of the sides of the palms with extension onto the fingers, periungual erythema with edema, and macular reddish-purple lesions on the volar surfaces of the fingers also may occur. Purpura may develop secondary to thrombocytopenia or necrotizing angiitis of small vessels. Photosensitivity occurs in 40% of patients.
Recurrent pleurisy, with or without effusion, is frequent. Lupus pneumonitis is rare, though minor pulmonary function abnormalities are common. Pericarditis is often present. A more serious complication in some patients is pulmonary hypertension.
Generalized adenopathy is frequent, particularly in children, young adults, and blacks. Splenomegaly occurs in 10% of patients. Histologically, the spleen may show periarterial fibrosis ("onion-skin" lesion). CNS involvement can cause headaches, personality changes, epilepsy, psychoses, and organic brain syndrome. Cerebral thrombosis, though rare, is now known to be associated with anticardiolipin antibodies.
Renal involvement may be benign and asymptomatic or relentlessly progressive and fatal. The most common manifestation is proteinuria. The histopathology of the renal lesion varies from a focal, usually benign, glomerulitis to a diffuse membranoproliferative glomerulonephritis. Since milder cases have been increasingly detected, the incidence of clinically significant renal disease has dropped.
Acute lupus hemophagocytic syndrome: A rare presentation of SLE, with fever and fulminant pancytopenia, has recently been described in Asians, among whom SLE has a much higher incidence. Bone marrow showed proliferation of reactive histiocytes, with phagocytosis of hemopoietic cells (an example of the reactive hemophagocytic syndrome). There was no evidence of underlying infection. Patients responded promptly to corticosteroids.
Laboratory Findings
The screening test for SLE is the fluorescent test for antinuclear antibodies (ANA); positive ANA tests (usually in high titer) are found in >98% of SLE patients. A positive ANA test should lead to the more specific test for anti-DNA antibodies (measured by the Farr test, or by the slightly less sensitive crithidia slide method). High titers of anti-DNA antibodies are almost specific for SLE.
A variety of other antinuclear, and also anticytoplasmic, antibodies (eg, Ro, La, Sm, RNP, Jo-1) are diagnostically valuable in connective tissue diseases. As Ro is predominantly cytoplasmic, anti-Ro antibodies may occasionally be found in ANA-negative SLE patients.
False-positive STS may be seen in 5 to 10% of SLE patients. They are associated with the lupus anticoagulant, which is manifested as a prolongation of partial thromboplastin time (PTT). Both those tests measure antiphospholipid antibodies such as anticardiolipin antibodies. These are associated with a tendency to thrombosis, abortion, and thrombocytopenia. Serum complement levels usually are depressed in active disease and are usually (though not necessarily) lowest in patients with active nephritis. C-reactive protein levels are strikingly low in SLE, even in the face of ESR elevations >100 mm/h. The ESR is elevated almost uniformly during active disease. Leukopenia is the rule, notably lymphopenia in active SLE. Hemolytic anemia may occur.
Kidney damage can become evident at any time, even when other features of SLE are absent. Kidney biopsy is usually not necessary for diagnosis but may be helpful to evaluate the course of renal disease and to guide medical therapy. Urinalysis may be repeatedly normal despite early renal involvement confirmed by biopsy, but should be repeated at 4- to 6-mo intervals while monitoring patients in apparent remission. Red cell and granular casts suggest more active nephritis.
Diagnosis
Recognition of SLE is obvious when a patient (particularly, a young woman) has a febrile disease with an erythematous skin rash, polyarthritis, evidence of renal disease, intermittent pleuritic pain, leukopenia, and hyperglobulinemia with anti-DNA antibodies. SLE can be difficult to differentiate from other connective tissue disorders in its early stages; eg, be mistaken for RA if arthritic symptoms predominate. Meticulous evaluation and long-term observation may be required before the diagnosis is established. Migraine, epilepsy, or psychoses may be initial findings. Patients with discoid lesions must be evaluated to differentiate discoid from systemic LE. Some drugs (eg, hydralazine, procainamide, and ? blockers) produce positive ANA tests and, occasionally, a lupus-like syndrome. These features disappear if the drug is withdrawn promptly.
The American College of Rheumatology (formerly, the American Rheumatism Association) has proposed criteria for the classification (but not for diagnosis) of SLE; 4 of the following are required: (1) malar rash; (2) discoid rash; (3) photosensitivity; (4) oral ulcers; (5) arthritis; (6) serositis; (7) renal disorder; (8) leukopenia (lesser 4000/µL), lymphopenia (lesser 1500/µL), hemolytic anemia, or thrombocytopenia ( lesser 100,000/µL); (9) neurologic disorder; (10) positive LE cell or anti-DNA or anti-Sm antibody or a false-positive STS; (11) antinuclear antibodies in raised titer.
Mixed connective tissue disease (MCTD) is a syndrome with clinical features of SLE over-lapping with those of progressive systemic sclerosis and polymyositis/dermatomyositis. The disorder is discussed separately, below.
Prognosis
This varies widely, depending on the organs involved and the intensity of the inflammatory reaction. The course of SLE is commonly chronic and relapsing, often with long periods (years) of remission. During the past 2 decades the prognosis has improved markedly. Provided the initial acute phase is controlled, the long-term prognosis is good. Flares are rare after the menopause. The 10-yr survival in most developed countries is >95%. This very improved prognosis underlines one lesson: In SLE, making the diagnosis is of paramount importance.
Treatment
Management of idiopathic SLE depends on the location and severity of the disease. To simplify therapy, SLE should be classified as mild (fever, arthritis, pleurisy, pericarditis, headaches, or rash) or severe (life-threatening disease; eg, hemolytic anemia, thrombocytopenic purpura, massive pleural and pericardial involvement, significant renal damage, acute vasculitis of the extremities or GI tract, or florid CNS involvement). The course is totally unpredictable. The following drugs and dosages are for adults, unless otherwise specified.
Mild or remittent disease may require little or no therapy. Arthralgias are usually controlled with nonsteroidal anti-inflammatory agents. Aspirin is useful, especially in patients with the thrombotic tendency associated with anticardiolipin antibodies, but high doses in SLE may cause liver toxicity. Antimalarials help, particularly when joint and skin manifestations are prominent. Regimens vary, but hydroxychloroquine 200 mg/day is preferred. Some advocate a loading dose of 400 mg/day, but this may cause diplopia, raising fears of ocular toxicity in the patient. Alternatives are chloroquine 250 mg/day or quinacrine (mepacrine) 50 to 100 mg/day. Combinations of these drugs are sometimes used. Ophthalmologic examination usually is advised at 6-mo intervals, though on these modest doses this practice may be excessively cautious, and recent data suggest that hydroxychloroquine has low retinal toxicity.
Severe disease requires immediate corticosteroid therapy. The suggested doses are for adults, but children may require almost as much. Starting prednisone dosages for specific manifestations are as follows: hemolytic anemia, 60 mg/day; thrombocytopenic purpura, 40 to 60 mg/day (platelet count may not rise for 4 to 6 wk); severe polyserositis, 20 to 60 mg/day (response begins within days); renal damage, 20 to 60 mg/day in combination with immunosuppressives. Improvement does not usually occur for 4 to 12 wk and may not be evident until corticosteroid dosage is reduced. A combination of prednisone with immunosuppressive agents now is recommended in active SLE or lupus nephritis. Azathioprine 2.5 mg/kg/day or cyclophosphamide 2.5 mg/kg/day is most often used, though there is a trend toward the use of intermittent immunosuppressives such as cyclophosphamide 500 mg IV, repeated as the blood count allows. One recommended regimen consists of 3 weekly "pulses" of 500 mg cyclophosphamide IV followed by 3 monthly "pulses."
Acute vasculitis and severe CNS lupus--the same regimens are used as for renal damage, above. In CNS lupus, methylprednisolone, 1000 mg by slow (1-h) IV infusion on 3 successive days often is the initial form of treatment, together with IV cyclophosphamide, as above.
In both mild and severe disease, after the inflammatory process is controlled, the minimal dose of corticosteroids and other agents necessary to suppress tissue inflammation must be determined. This usually is done by decreasing the dose by 10% at intervals (depending on how fast clinical improvement occurs). For example, if fever and arthritis are the initial active manifestations, the dose is reduced at weekly intervals; if thrombocytopenia or renal disease (both of which respond more slowly to initiation of therapy) are problems, reductions are made q 2 to 4 wk. Rebound (temporary flare) and relapse tend to occur in the system with the most recent exacerbation. Response to therapy is measured by relief of symptoms and signs or improvement in laboratory tests. Anti-DNA antibody titers and/or low serum complement may or may not return toward normal with treatment. Clinical rather than serologic features are all-important in determining therapy. Below 15 mg of prednisone daily, a gradual change to alternate-day dosage may be possible. The majority of SLE patients can ultimately be weaned off prednisone.
General medical management: Intercurrent infection, often complicating the disease and easily mistaken for some of its manifestations, should be treated vigorously. The usual measures to combat heart failure and renal insufficiency must be taken, in addition to using anti-inflammatory agents. Close medical supervision is imperative during surgical procedures and pregnancy. Hypersensitivity rashes are common with sulfonamides, trimethoprim/sulfamethoxazole, and penicillin. Flares may occur with oral contraceptives but are rare. Anticoagulation is vital in those patients with antiphospholipid antibodies and recurrent thrombosis. Provided that renal and cardiac functions are adequate, pregnancy is not contraindicated in SLE; however, spontaneous abortion and postpartum disease flares are frequent. The latter usually are easily controlled, given increased vigilance in the puerperium. Patients with antiphospholipid antibodies may suffer from recurrent spontaneous abortion due to placental vessel thrombosis and ischemia. Successful treatment has been reported with corticosteroids (up to 30 mg prednisone daily) or anticoagulation with low-dose aspirin or heparin. Many comparative trials are in progress in the management of these high-risk pregnancies, and as yet there is no consensus on the most successful treatment.
Perhaps the greatest change in the management of SLE during the past 2 decades has been in attitude--the realization that for most patients, the disease can be controlled without recourse to heroic doses of corticosteroids.
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