Criterion	Definition
1. Malar rash	Fixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial folds
2. Discoid rash	Erythematous raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur in older lesions
3. Photosensitivity	Skin rash as a result of unusual reaction to sunlight by patient history or physician observation
4. Oral ulcers	Oral or nasopharyngeal ulceration, usually painless, observed by physician
5. Nonerosive arthritis	Involving two or more peripheral joints, characterized by tenderness, swelling, or effusion
6. Pleuritis or pericarditis	1. Pleuritis—convincing history of pleuritic pain or rubbing heard by a physician, or evidence of pleural effusion OR 2. Pericarditis—documented by electrocardiogram (ECG) or rub or evidence of pericardial effusion
7. Renal disorder	1. Persistent proteinuria >0.5 g/day, or >3+ if quantitation not performed OR 2. Cellular casts—may be red cell, hemoglobin, granular, tubular, or mixed
8. Neurologic disorder	1. Seizures—in the absence of offending drugs or known metabolic derangements (e.g., uremia, ketoacidosis, electrolyte imbalance) OR 2. Psychosis—in the absence of offending drugs or known metabolic derangements (e.g., uremia, ketoacidosis, electrolyte imbalance)
9. Hematologic disorder	1. Hemolytic anemia—with reticulocytosis OR 2. Leukopenia—<4000/mm³ total on two or more occasions OR 3. Lymphopenia—<1500/mm³ on two or more occasions OR 4. Thrombocytopenia—<100,000/mm³ in the absence of offending drugs
10. Immunologic disorder	1. Anti-DNA—antibody to native DNA in abnormal titer OR 2. Anti-Sm—presence of antibody to Sm nuclear antigen OR 3. Positive finding of antiphospholipid antibodies on: 1. An abnormal serum level of IgG or IgM anticardiolipin antibodies 2. A positive test result for lupus anticoagulant using a standard method 3. A false-positive test result for at least 6 mo and confirmed by Treponema pallidum immobilization or fluorescent treponemal antibody absorption test Standard methods should be used in testing for the presence of antiphospholipids.
11. Positive antinuclear antibody	An abnormal titer of antinuclear antibody by immunofluorescence or an equivalent assay at any point in time and in the absence of drugs known to be associated with drug-induced lupus syndrome

From Hochberg MC: Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus (letter), Arthritis Rheum 40:1725, 1997 and The American College of Rheumatology www.rheumatology.org 2012.

Different Forms of Lupus

There are several forms of lupus, including discoid, systemic, drug-induced, and neonatal lupus.

Discoid (cutaneous) lupus is always limited to the skin and is identified by biopsy of the rash that may appear on the face, neck, and scalp. Discoid lupus does not generally involve the body’s internal organs but can evolve into the systemic form of the disease, even if treated. Evolution to systemic lupus cannot be predicted or prevented. The antinuclear antibody (ANA) test may be negative or positive at a low titer. Discoid lupus accounts for approximately 10% of all cases of lupus.

Systemic lupus is usually more severe than discoid lupus and can affect the skin, joints, and almost any organ or body system, including the lungs, kidneys, heart, and brain. Systemic lupus may include periods in which few, if any, symptoms are evident (remission) and other times when the disease becomes more active (flare). Most often, when people mention “lupus,” they are referring to the systemic form of the disease. Approximately 70% of lupus cases are systemic. In about 50% of these cases, a major organ will be affected.

Drug-induced lupus occurs after the use of certain prescribed drugs (Box 29-1). The most frequently used drugs associated with drug-induced lupus are hydralazine hydrochloride and procainamide hydrochloride. Factors such as the rate of drug metabolism, the drug’s influence on immune regulation, and the host’s genetic composition are all believed to influence pathogenesis. Some drugs (e.g., oral contraceptives, isoniazid) induce serum antinuclear antibodies (ANAs) without symptoms. High antibody titers may exist for months without the development of clinical symptoms.

Box 29-1 Drugs That Can Produce Clinical and Serologic Features of Systemic Lupus Erythematosus

• Antiarrhythmics (e.g., procainamide hydrochloride)

• Anticonvulsants (e.g., phenytoin)

• Antihypertensives (e.g., hydralazine hydrochloride)

• Miscellaneous (e.g., chlorpromazine, isoniazid, penicillin, sulfonamides)

Procainamide-induced disease does not induce antibodies to double-stranded deoxyribonucleic acid (dsDNA). The ANAs in the drug-induced syndromes are histone-dependent and are never the only ANAs present in the blood. Even with discontinuation of the drug, antibody titers usually remain elevated for months or years.

Only about 4% of patients who take these drugs will develop the antibodies suggestive of lupus. Of those 4%, only an extremely small number will develop overt drug-induced lupus. The symptoms of drug-induced lupus are similar to those of systemic lupus, but milder. Patients with drug-related lupus have a predominance of pulmonary and polyserositic signs and symptoms. Patients with drug-induced lupus have no associated renal or central nervous system (CNS) disease. In addition, lupus-inducing drugs do not appear to exacerbate idiopathic SLE. The symptoms usually fade when the medications are discontinued.

Neonatal lupus is a rare condition acquired from the passage of maternal autoantibodies, specifically anti-Ro/SS-A or anti-La/SS-B, that can affect the skin, heart, and blood of the fetus and newborn. Neonatal lupus is associated with a rash that appears within the first several weeks of life and may persist for about 6 months before disappearing. Congenital heart block can occur but is much less common than a rash. Neonatal lupus is not systemic lupus.

Etiology

The cause of SLE is unknown (idiopathic). Although no single causative agent has been identified, a primary defect in the regulation of the immune system is considered important in the pathogenesis of the disorder. Genetic predisposition can be a factor. Hormones and environmental factors that may trigger the disease include infections, antibiotics (especially sulfonamides and penicillin derivatives), ultraviolet (UV) light, extreme stress, and certain drugs. A combination of these factors may be synergistic.

Antibodies directed against T lymphocytes, including the membrane molecules that mediate their responses, are regularly detected in patients with SLE. Their role in the pathogenesis of autoimmunity is still unclear.

Epidemiology

Lupus can occur at any age and in either gender, although it occurs 10 to 15 times more frequently in women than in men after puberty. The Lupus Foundation of America estimates that approximately 1.4 million Americans have a form of lupus. The overall incidence of SLE is estimated to be 50 to 70 new cases/year/1 million population.

Racial groups such as blacks, Native Americans, Puerto Ricans, and Asians (particularly Chinese) demonstrate an increased frequency of SLE. Lupus is two to three times more prevalent among people of color. The incidence of SLE in black women between the 20 and 64 years old is 1 in 245. The reasons for ethnic differences are not clear.

The prevalence rate, based on a total population, is 1 in 2000, but it is 1 in 700 for women between 20 and 64 years old; 80% of those with systemic lupus develop it between ages 15 and 45 years.

Survival is estimated to be higher than 90% at 10 years after diagnosis. The highest mortality rate is in patients with progressive renal involvement or CNS disease. The two most frequent causes of death are renal failure and infectious complications.

Signs and Symptoms

SLE is a disease of acute and chronic inflammation. Symptoms of SLE often mimic other, less serious illnesses. Fever is one of the most common clinical manifestations of SLE. Disease activity accounts for more than 66% of febrile episodes in patients with SLE. Antibodies with elevated titers that are characteristic of lupus disease activity rather than infection include anti-dsDNA and anti–ribosomal P antibodies, as well as reduced levels of complement and leukopenia.

Many of the clinical manifestations of SLE are a consequence of tissue damage from vasculopathy mediated by immune complexes. Other conditions (e.g., thrombocytopenia, antiphospholipid syndrome) are the direct effects of antibodies to cell surface molecules or serum components.

Manifestations of the disease range from a typical mild illness limited to a photosensitive facial rash and transient diffuse arthritis to life-threatening involvement of the CNS or renal, cardiac, or respiratory system (Fig. 29-1). In the early phases, it is often difficult to distinguish SLE from other systemic rheumatic disorders, such as progressive systemic sclerosis (PSS), polymyositis, primary Sjögren’s syndrome, primary Raynaud’s phenomenon, and rheumatoid arthritis. Polyarthritis and dermatitis are the most common clinical manifestations.

Figure 29-1 Signs and symptoms of systemic lupus erythematosus (SLE).

The course of the disease is highly variable. It usually follows a chronic and irregular course, with periods of exacerbations and remissions. Clinical signs and symptoms can include fever, weight loss, malaise, arthralgia (joint pain) and arthritis (inflammation of the joints), and the characteristic erythematous, maculopapular (“butterfly”) rash over the bridge of the nose (Table 29-2). In addition, there is a tendency toward increased susceptibility to common and opportunistic infections. Multiple organ systems may be affected simultaneously.

Table 29-2

Systemic Lupus Erythematosus Symptoms

Symptom	Percentage of Cases
Achy joints (arthralgia)	95
Frequent fevers >37.8° C (100° F)	90
Arthritis (swollen joints)	90
Prolonged or extreme fatigue	81
Skin rashes	74
Anemia	71
Kidney involvement	50
Pain in the chest on deep breathing (pleurisy)	45
Butterfly-shaped rash across the cheek and nose	42
Sun or light sensitivity (photosensitivity)	30
Hair loss	27
Abnormal blood clotting problems	20
Raynaud’s phenomenon (fingers turning white and/or blue in the cold)	17
Seizures	15
Mouth or nose ulcers	12