Perspective

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with widespread physical effects caused by the production of autoantibodies to components of cellular nuclei.¹ The term lupus (Latin for “wolf”) is attributed to the 13th-century physician Rogerius, who used it to describe the characteristic facial lesions that were reminiscent of a wolf’s bite.

In some patients the illness is mild. Other patients suffer early, catastrophic organ damage. Early deaths are frequently due to injury to the kidney and brain. Later deaths often occur as a result of acute myocardial infarction, stroke, or infection. Steroids used for treatment may cause or worsen complications.

Epidemiology

SLE is more common by a ratio of 12 : 1 in women aged 15 to 45 years and by a ratio of 2 : 1 in younger and older women. The overall prevalence of this disease is about 1 in 1000. In most studies of SLE, about 90% of enrollees are women. In the United States, the disease is three times more common in black women than in white women. In addition to genetic factors, age, sex, race, and socioeconomic status have an impact on disease expression and prognosis. With optimal management, the 20-year survival rate approaches 70% and the 1-year survival rate is about 90%.²

Pathophysiology

SLE is a prototypic autoimmune disease characterized by tissue damage from excessive antibody production and immune complex deposition. The chronic inflammation characteristic of the disease originates from overproduction of autoantibodies and failure of the body to suppress them.

Nearly every tissue in the body can be affected. Autoantibodies directly react to human antigens, immune complexes are deposited in tissue and blood vessels, and the complement cascade is activated, which results in inflammation and organ damage.

The exact cause is unknown, but genetic predisposition, viruses, ultraviolet light (including sunlight), and medications such as hydralazine, isoniazid, and procainamide are known to be involved in certain patients. There is a relationship to specific human leukocyte antigen genotypes.

Autoantibodies to lupus erythematosus are found in laboratory workers who handle lupus sera. Exposure to certain drugs can produce a SLE-like syndrome. Hormonal factors include an association with estrogens, which may explain the higher prevalence in women.

Presenting Signs and Symptoms

The triad of fever, joint pain, and rash in a woman of childbearing age suggests SLE. The most well-recognized cutaneous finding is the red, raised butterfly rash (Fig. 108.1), but malaise, fatigue, aches, fever, and weight loss are the most common symptoms. The rash, which does not cross the nasolabial fold, may be painful or pruritic. It may be precipitated by sunlight and can last from days to weeks.

Fig. 108.1 Erythematous malar rash of systemic lupus erythematosus.

Note that the rash does not cross the nasolabial fold.

(From Gladman DD, Urowitz MB. Clinical features. In: Hochberg MC, Silman AJ, Smolen JS, editors. Rheumatology. Philadelphia:, Mosby; 2003. pp. 1359–79.)

More than two thirds of patients have vague constitutional symptoms. A thorough evaluation is required before attributing such symptoms to lupus alone. Patients can have kidney failure, infections, adrenal failure, and other complications with similar symptoms (Box 108.1).

See Box 108.1, Criteria for the Classification of Systemic Lupus Erythematosus, online at www.expertconsult.com

Clinical manifestations range widely from mild to life-threatening. About half of patients have severe disease, defined as complications that threaten life or organ function.

Some rash or arthritis (or both) develops in a substantial majority of patients. At least half of patients have the Reynaud phenomenon, mucous membrane involvement, and renal or central nervous system involvement. About half of patients report photosensitivity. Pleurisy, vasculitis, or gastrointestinal involvement will develop in a quarter to a third of patients. Less common but important manifestations include pancreatitis, myositis, and myocarditis.

Differential Diagnosis and Medical Decision Making

Treatment

Medical therapy attempts to reduce inflammation, suppress the immune system, and control pain. Nonsteroidal antiinflammatory drugs (NSAIDs), corticosteroids, and immunosuppressive agents are the mainstays of treatment. Aspirin and other NSAIDs are the primary treatment of arthralgias, pleurisy, and pericarditis. The maximum standard recommended doses of these agents are usually needed. These agents should be avoided in patients with severe gastrointestinal complications, renal insufficiency, nephritis, or thrombocytopenia. Treatment with NSAIDs can worsen lupus nephritis, either by causing interstitial nephritis or by inhibiting prostaglandins.⁵

Topical corticosteroids control most rashes. Although antiinflammatory and antimalarial drugs are often advocated for patients with minor symptoms to avoid the long-term complications of corticosteroid therapy, symptoms such as arthralgias, fatigue, pleurisy, and others may require lower-dose steroids, such as prednisone (0.5 mg/kg or less).

High-dose steroids (e.g., 1 mg/kg/day of prednisone or 1 g of methylprednisolone intravenously [IV]) are used when major organs are involved and also for hemolytic anemia and severe thrombocytopenia. For example, in patients with lupus-related cerebritis or acute worsening of lupus nephritis, 1 g/day of methylprednisolone IV may be given for several days.

Corticosteroids are associated with well-known complications, including steroid-induced diabetes, osteoporosis, weight gain, pancreatitis, osteonecrosis, accelerated atherosclerosis, and immunosuppression. Patients receiving chronic steroid therapy should be evaluated promptly for any episode of fever or potential infection. When patients who are taking corticosteroids have an acute serious illness or other physiologic stress (e.g., surgery, childbirth), they should also be given hydrocortisone (100 mg IV every 8 hours). Patients with overwhelming sepsis or shock should be given stress-dose steroids (e.g., 100 mg of hydrocortisone IV), in addition to the usual treatment with broad-spectrum antibiotics and intravenous resuscitation fluid.

Antimalarial drugs are effective for the cutaneous and musculoskeletal manifestations of SLE. Hydroxychloroquine and chloroquine are given on an outpatient basis in a loading dose for 4 weeks, followed by maintenance dosing once the symptoms are under control. Withdrawal of the drug may result in flare of the disease.

Immunosuppressive agents (azathioprine, methotrexate, cyclophosphamide) are reserved for patients with severe renal or cerebral disease in whom other therapies have failed and for patients who cannot tolerate corticosteroids. Studies of the use of immunosuppressants have shown decreased chronic renal scarring and a reduced likelihood of end-stage renal disease without an increase in mortality. The toxic effects of such drugs are numerous and include myelosuppression, risk for neoplasms, and infections,⁶ especially with gram-negative organisms, encapsulated gram-positive organisms, herpes zoster, and opportunistic organisms. Febrile patients who are taking azathioprine, methotrexate, or cyclophosphamide should be admitted regardless of whether a source is evident because gram-negative or streptococcal sepsis occurs in this population. Immunosuppressed patients with localized herpes zoster should be admitted for intravenous acyclovir treatment to prevent viral dissemination.

follow-up, next steps in care, and patient education

Patients with known disease and increasing arthritic pain or with a mild flare and no fever may be treated with NSAIDs or corticosteroids as an outpatient. Pleuritis and arthralgias can be treated on an outpatient basis. It may be prudent to perform urinalysis to ensure that there is no evidence of renal involvement, which might signal significant disease activity. In the absence of major organ involvement, the patient can be scheduled for prompt follow-up with a rheumatologist.

Patients with a new diagnosis of pericarditis, myocarditis, pleural effusion, or infiltrates or with evidence of vasculitis or renal insufficiency should almost always be admitted to the hospital. If there is uncertainty regarding diagnosis or severity of any circumstance, patients should be admitted for observation, testing, and treatment. Patients with worsening disease who are taking large doses of steroids or immunosuppressive agents should be admitted for aggressive treatment.

Patients with evidence of lupus nephritis and worsening renal failure should be admitted for therapy with steroids and, frequently, immunosuppressive agents.⁶ The serum creatinine level may be elevated, but serious disease may be present even with normal creatinine levels. Proteinuria may be present, or red blood cell casts in urine may be the only sign of severe renal involvement.

Patients with SLE have a higher risk for coronary artery disease, so a complaint of chest pain should prompt evaluation for cardiac ischemia. If pericarditis is suspected, evaluation for pericardial effusion may be necessary, although tamponade is rare. Patients with myocarditis should be observed for evidence of congestive heart failure and dysrhythmias.

Shortness of breath suggests lung infection from typical or atypical organisms. Opportunistic infection, tuberculosis, and lupus pneumonitis need to be considered. In a hypoxic patient, it is prudent to consider the possibility of pulmonary embolism secondary to antiphospholipid antibody with thrombosis. Patients with significant pleural effusions should be admitted for consideration of diagnostic thoracentesis and treatment. Pleural effusions may be complicated by infection, tuberculosis, or malignancy.

SLE predisposes patients to anemia and thrombocytopenia. Patients should be admitted if there is evidence of active hemolysis with decreased hematocrit levels or hemolysis that is evident on the blood smear. Patients with thrombocytopenia should be admitted if evidence of bleeding is seen or if platelet counts are severely decreased (<50,000/mm³). If the patient is actively bleeding, platelet transfusion is appropriate; however, rapid destruction of the platelets may occur. Simultaneous administration of intravenous corticosteroids and gamma globulin will aid in increasing the platelet count and decreasing the amount of platelet destruction.

Patients with evidence of arterial or venous thrombosis should be admitted for anticoagulation and possible embolectomy. Anticoagulation can be achieved acutely with heparin, although large doses are occasionally needed to overcome the antibody effect. The partial thromboplastin time (PTT), if not elevated, can be monitored to assess for evidence of adequate anticoagulation, with careful observation for bleeding in patients who are also thrombocytopenic. Otherwise, patients with a prolonged PTT and evidence of lupus anticoagulant can be monitored with thrombin times if necessary. Patients with an international normalized ratio of less than 2.5 should nevertheless be considered to have a possible thrombus if they have a history of antiphospholipid syndrome.

Pregnant patients should undergo early follow-up with a high-risk obstetrician. Emergency delivery for a pregnant patient with SLE should include stress-dose steroid administration and close observation of the neonate for congenital complete heart block (i.e., neonatal lupus). Emergency cardiac pacing may be necessary for the infant.