SLE

Introduction

Background

Systemic lupus erythematosus (SLE) is a chronic inflammatory disease of unknown cause that affects multiple organ systems. Immunologic abnormalities, especially the production of a number of antinuclear antibodies, are another prominent feature of this disease. The clinical course is marked by spontaneous remissions and relapses. Its multisystemic manifestations and the complications from the use of immunosuppressive agents make the diagnosis and management of this entity challenging.

Pathophysiology

Autoantibodies, circulating immune complexes, and T lymphocytes all contribute to the expression of disease. Organ systems affected include dermatologic, serous membranes, renal, central nervous system (CNS), hematologic, musculoskeletal, cardiovascular, pulmonary, vascular endothelium, and gastrointestinal. The diagnosis of SLE is made if 4 or more of the following manifestations are present, either serially or simultaneously (specificity, 95%; sensitivity, 75%):

• Malar rash
• Discoid rash
• Photosensitivity
• Oral ulcers
• Arthritis
• Serositis
• Renal disorder
• Neurologic disorder
• Hematologic disorder
• Immunologic disorder
• Antinuclear antibody

Frequency

United States

In the United States, the annual incidence of SLE ranges from 6-35 per 100,000 population. The incidence of SLE in black women is approximately 4 times higher than in white women. SLE is more frequent in Asian women as well.

The reported prevalence of SLE in the population is 40-50 cases per 100,000 population.

International

In England, the incidence is 200 cases per 100,000 women (aged 18-65 y).

Mortality/Morbidity

Recent studies in Europe and Canada have shown a gradual increase in mortality the longer the patient has the disease, from greater than 90% of patients surviving more than 5 years to 10-year and 20-year survival rates of 75-85% and 70%, respectively.

• Early deaths usually are caused by active disease. Atherosclerosis is a leading cause in late deaths. Infection and nephritis are major causes of mortality in all stages of SLE.
• After dialysis or transplantation, a reduction in disease activity and flares has been reported.
• Thrombosis, often secondary to antiphospholipid syndrome and a hypercoagulable state, carditis, pneumonitis, pulmonary hypertension, stroke, myocardial infarction, and cerebritis cause severe morbidity and mortality.

Race

The prevalence of SLE is higher among Asians, African Americans, African Caribbeans, Hispanic Americans, and Asian Indians in Great Britain. In comparison, SLE occurs infrequently in blacks in Africa.

In New Zealand, the prevalence and mortality of SLE are higher in Polynesians than in whites.

In France, SLE is more common among immigrants from Spain, Portugal, North Africa, and Italy.

Sex

The frequency of SLE among women is increased and has been attributed to an estrogen hormonal effect.

In children in whom sex hormone effects are presumably minimal, the female-to-male ratio is 3:1. In adults, the female-to-male ratio ranges from 10-15:1. In older individuals, the female-to-male ratio is approximately 8:1.

Age

Sixty-five percent of patients with SLE have disease onset between the ages of 16 and 55 years. Of the remaining cases, 20% present before age 16 years and 15% after age 55 years.

Clinical

History

Manifestations are diverse, and the mean length of time between onset of symptoms and diagnosis is 5 years. The disease is characterized by exacerbations and remissions. Many women relate flares of their lupus to the postovulatory phase of the menstrual cycle, with resolution of symptoms at the time of menses.

• Constitutional symptoms include low-grade fever, fatigue, malaise, anorexia, nausea, and weight loss. The initial presentation may involve one or more organ systems.
• Arthralgia occurs in more than 90% of the patients and is the initial complaint in many patients. Often, the pain is out of proportion to physical findings.
• A malar, butterfly rash over the cheeks and bridge of the nose (55-90%) with photosensitivity to ultraviolet (UV) light has been reported (mostly in whites). It also often involves the chin and ears. It lasts for a few days and tends to recur.
• Painful or painless ulcers in the nose and mouth are frequent complaints. Perforation of the nasal septum occurs infrequently.
• Neurologic symptoms include mild cognitive defects, organic brain syndromes, delirium, psychosis, seizures, headache, and/or neuropathies. Any region of the brain, meninges, spinal cord, and cranial and peripheral nerves can be involved. CNS events often occur when SLE is active in other organ systems.
• Psychosis, related to SLE or to high-dose steroids, is one of the psychiatric manifestations of SLE. If the psychosis is unaffected after stopping the steroid, then it is most likely related to the disease process.
• Pleuritic pain, dyspnea, cough, fever, and chest pain are important cardiopulmonary complaints.
• Patients may present with abdominal pain, diarrhea, and vomiting. Intestinal perforation and vasculitis are important diagnoses to exclude.
• A number of other conditions seen more frequently with SLE include the following:
  • Stroke
  • Pulmonary embolus
  • Deep venous thrombosis (DVT)
  • Acute ischemia
  • Retinal vasculitis

Physical

• Fever is a challenging problem in systemic lupus erythematosus (SLE). It can be a manifestation of active lupus or a representation of infection, malignancy, or drug reaction. Temperature higher than 102°F should prompt a search for infection. Lower-grade temperature is observed in patients on immunosuppressive agents.
• Malar rash is a fixed erythema that spares the nasolabial folds. It is a butterfly rash that can be flat or raised over the cheeks and bridge of the nose. It also often involves the chin and ears.
• Discoid rash occurs in 20% of patients with SLE and can result in disfiguring scars. The discoid rash can present as erythematous patches with keratotic scaling over sun-exposed areas of the skin. Systemic manifestations of SLE may be absent.
• Alopecia or loss or loss of hair may occur.
• All patients experience painless or painful oral or vaginal ulcers, which are helpful in making the diagnosis, during the course of their illness.
• Gastrointestinal findings include vague abdominal discomfort, nausea, and diarrhea. Acute crampy abdominal pain, vomiting, and diarrhea may signify vasculitis of the intestine.
• Joint findings
  • Tenderness, edema, and effusions accompany a polyarthritis that is symmetric, nonerosive, and usually nondeforming. The arthritis frequently involves the proximal interphalangeal (PIP) and metacarpophalangeal (MCP) joints of the hands as well as the wrists and knees.
  • Consider avascular necrosis, which is common in patients who are taking glucocorticoids.
  • In addition, consider septic arthritis when one joint is inflamed out of proportion to all other joints.
• Central nervous system findings
  • All types of seizures have been reported; the most frequent is the grand mal seizure. Sensory or sensorimotor neuropathies are also common.
  • Incidence of stroke is high in the first 5 years of disease. Patients with antiphospholipid antibodies are at higher risk for such events.
• Funduscopic examination is important in patients with visual complaints. Retinal vasculitis can lead to blindness and is demonstrated by sheathed narrow retinal arterioles with white exudates adjacent to the vessels.
• The renal system can be affected leading to renal failure. Specific signs and symptoms of renal disease may not be apparent until advanced nephrotic syndrome or renal failure is present; therefore, obtaining a urine analysis and serum BUN and creatinine levels on a regular basis is important.
• Cardiovascular system findings
  • Atherosclerosis occurs prematurely in patients with SLE and is an independent risk factor for cardiovascular disease.
  • Pulmonary hypertension, vasculitis with digital infarcts, and splinter hemorrhages may be observed.
  • Systolic murmurs are reported in up to 70% of cases. They may be secondary to fever, hypoxia, anemia, or Libman-Sacks endocarditis (associated with antiphospholipid antibodies).
  • Pericarditis has an incidence of 20-30% and is the most common presentation of heart involvement. It is usually associated with small effusions, but it may involve larger effusions when uremia is concomitant. Myocarditis can cause heart failure, arrhythmias, and sudden death.
• Pulmonary findings
  • Tachypnea, cough, and fever are common manifestations of lupus pneumonitis.
  • Hemoptysis may signify pulmonary hemorrhage secondary to the disease. However, infection is the most common cause of infiltrates seen on radiographs.

Causes

• Many of the clinical manifestations of SLE are caused by the effects of circulating immune complexes on various tissues or to the direct effects of antibodies to cell surface components.
• Whether polyclonal B-cell activation or a response to specific antigens exists is unclear.
• Cytotoxic T cells and suppressor T cells (which would normally downregulate immune responses) are decreased.
• The generation of polyclonal T-cell cytolytic activity is impaired.
• Helper (CD4⁺) T cells are increased.
• A lack of immune tolerance is observed in animal models.
• A high concordance rate (14-57%) of SLE is noted in monozygotic twins. Each patient manifests his or her disease differently.
• Five to twelve percent of relatives of patients with SLE have the disease.
• If a mother has SLE, her daughter's risk of developing the disease is 1:40, and her son's risk is 1:250.
• Administration of estrogen to postmenopausal women appears to double the risk of developing SLE.
• Breastfeeding is associated with a decreased risk of developing SLE.
• Viruses, for example, may stimulate specific cells in the immune network. Patients with SLE also have higher titers of antibodies to Epstein-Barr virus (EBV), have increased circulating EBV viral loads, and make antibodies to retroviruses, including to protein regions homologous to nuclear antigens.
• Trypanosomiasis or mycobacterial infections may induce anti-DNA antibodies or even lupuslike symptoms, and lupus flares may follow bacterial infections.
• Silica dust and cigarette smoking may increase the risk of developing SLE.
• Photosensitivity is clearly a precipitant of skin disease.
• The presence of antiphospholipid antibodies in patients dictates a constellation of signs caused by thrombosis.