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Systemic lupus erythematosus

Description

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of autoantibodies to components of the cell nucleus in association with pleiomorphic clinical manifestations involving almost all organ systems.  SLE is a complex multisystem disease with variable presentations, course, and prognosis as well as remissions and flares.

Clinical Manifestations

The diversity of presentations, accumulation of manifestations over time and changeable course of lupus can challenge even the most astute of clinicians.  In an effort to overcome the lack of a pathognomonic test, account for the complexity of SLE and mitigate the potential for considerable heterogeneity of patients who might be enrolled in clinical trials, the American College of Rheumatology developed a set of classification criteria in 1971, which was subsequently revised in 1982 and again in 1997.  These criteria reflect the major clinical features of disease and incorporate some of the associated laboratory findings (Table 1).   The presence of four or more criteria is required to classify a patient as having SLE. 

Table 1.  Systemic Lupus Erythematosus Classification Criteria 

Malar rash

Discoid rash  

Photosensitivity        

Oral ulcers

Arthritis

Serositis

Renal disorder

  1. > 0.5 g/d proteinuria, or
  2. ? 3+ dipstick proteinuria, or
  3. Cellular casts

Neurologic disorder

  1. Seizures
  2. Psychosis (without other cause)

Hematologic disorder

  1. Hemolytic anemia, or
  2. Leukopenia (< 4000/µL), or
  3. Lymphopenia (< 1500/µL), or
  4. Thrombocytopenia ( < 100,000/µL)

Immunologic disorder

  1. Antibody to native DNA, or
  2. Antibody to Sm, or
  3. Positive test for antiphospholipid antibodies, including: (1) abnormal IgG or IgM anticardiolipin antibody level, (2) lupus anticoagulant, (3) false-positive serologic test for syphilis

Positive antinuclear antibodies

Early signs and symptoms of SLE may be nonspecific and a delay in diagnosis is not uncommon.  Early signs and symptoms can include fever, fatigue, hair loss, anemia, arthralgias, and weight loss.  Some forms of organ system involvement such as rash or arthritis are common, particularly at the onset of the disease, but many systems may be involved and variable combinations of manifestations can occur.  Thus, it is only with a high index of suspicion, a careful history and physical examination and appropriate laboratory confirmation that a diagnosis of SLE is obtained.

Red Flags

The malar rash of lupus is red or purplish and can be mildly scaly.  It has the shape of a butterfly and involves the bridge of the nose as well as the malar area of the cheeks.  Most importantly, the rash spares the naso-labial folds of the face.

The arthritis of lupus tends to be migratory and involvement is usually symmetrical and polyarticular with the knees, carpal joints and small joints of the hands, especially the interphalangeal joints commonly affected.  The arthritis of lupus is considered to be non-deforming and non-erosive, unlike the arthritis of rheumatoid arthritis.  However, ligamentous laxity can occur over time.  This can result in flexion deformities, ulnar deviation, and swan neck deformities in the hands that can be confusing for the clinician trying to distinguish lupus from RA.  However, in lupus these deformities are usually not fixed and are easily reducible, meaning that the examiner can easily move the joints into proper alignment.  The hand deformities in lupus patients resemble Jaccoud’s arthropathy, a non-erosive chronic deforming arthritis that may follow acute rheumatic fever.

Epidemiology

Prevalence rates in SLE are estimated to range from 20 to 150 cases per 100,000 in the United States.

Women are affected around nine times more often than men.

Men tend to suffer from more severe disease.

African-Americans and Hispanics are affected more frequently than whites and have higher disease morbidity.

65% have disease onset between ages 16 and 55, 20% present before age 16, and 15% present after the age of 55.

Pathology and pathophysiology

The pathologic findings of SLE are manifested by inflammation, blood vessel abnormalities that encompass bland vasculopathy and vasculitis, and immune complex deposition. 

The best characterized pathology involves the kidney, which display increases in mesangial cells and mesangial matrix, inflammation, cellular proliferation, basement membrane abnormalities, and immune-complex deposition.

Skin lesions in SLE often demonstrate inflammation and vacuolar degeneration at the dermal-epidermal junction.  In these lesions, granular deposits of IgG and complement components occur in a band-like pattern on immunofluorescence microscopy.   

Verrucous endocarditis, known as Libman-Sacks endocarditis, is a classic cardiac pathologic finding of SLE and is manifested by vegetations especially at the mitral valve.  These vegetations are accumulations of immune complexes, inflammatory cells, fibrin and necrotic debris.

Occlusive vasculopathy with venous and arterial thrombosis is another common pathologic finding in SLE.  Abnormal coagulation can result from intravascular inflammation and autoantibodies involved in immune complex reactions that may trigger thrombotic events.

Lupus occurs when predisposing genetic factors activated by environmental factors, drugs, or infectious agents result in a situation whereby the regulatory and suppressor T cells of the immune system are overwhelmed and malfunction.  Defects in tolerance, cell signaling, and apoptosis lead to an increase in B cells and autoantibody formation.  The inability of the reticuloendothelial system to adequately clear circulating immune complexes leads to additional inflammation and deposition of the immune complexes into tissue.  The chronicity of these processes leads to organ damage.  

 

Differential diagnosis

Given the diverse manifestations of SLE, the differential diagnosis is correspondingly broad and beyond the scope of this chapter to provide a comprehensive list of possible alternative diagnoses.  Some considerations include rheumatoid arthritis, undifferentiated connective tissue disease, primary Sjogren’s syndrome, antiphospholipid antibody syndrome, fibromyalgia with positive ANA, idiopathic thrombocytopenic purpura, and autoimmune thyroid disease.

The differential in patients presenting with fever, splenomegaly and lymphadenopathy should include infectious diseases, sarcoidosis and lymphoma. 

In patients presenting with glomerulonephritis, the differential diagnosis includes post-infectious glomerulonephritis (streptococcal, staphylococcal, subacute bacterial endocarditis, or hepatitis C), membranoproliferative glomerulonephritis, and renal vasculitis (antineutrophilic cytoplasmic antibody or anti-glomerular basement membrane associated).

Etiology

There is no known single cause of systemic lupus erythematosus.  Multiple predisposing factors have been identified.  The genetic predisposition is complex, as SLE is a polygenic disorder.  At least eight different chromosomal regions, especially on chromosome 1, contain susceptibility genes.  Certain HLA specificities (e.g. DR2, DR3, DR4, DR8) increase the risk for SLE and are present in 75% of individuals with the disease.  They predispose to autoimmunity because they determine which peptides can be presented to T-lymphocytes to activate help for autoantibody production and T-mediated immune responses.  Additional genetic risk factors include homozygous deficiency of C1q complement, certain Fc gamma receptor genes (involved in immune complex clearance and lupus nephritis), alleles of cytokines and chemokines, and alleles of protein tyrosine phosphatase gene (PTPN 22).

Hormones play a role given that around 90% of lupus patients are female.  Estrogens are thought to be permissive for autoimmunity.  Estradiol may prolong the life of autoreactive B and T lymphocytes.

Environmental factors may play a role in the onset of SLE and also in triggering flares.  The most recognized environmental trigger is ultraviolet light exposure.  Ultraviolet light alters the structure of DNA in the dermis which renders it more immunogenic.  Noninfectious agents linked with lupus include silica exposure, tobacco smoke, and, possibly, certain hair dyes, pesticides, allergens, food, heavy metals, and solvents. 

Lupus has been reported after a patient suffers from an infectious process.  Infections can also cause flares in the patient with  lupus.  Some lupus patients have demonstrated increased autoantibodies to retroviruses and viruses in the Epstein-Barr family.

Certain drugs have been implicated in causing drug-induced lupus.  Examples include isoniazid, procainamide, hydralazine, minocycline and anti-tumor necrosis factor agents.  Drug-induced lupus is often characterized by rash, fever and hematologic abnormalities but does not usually involve the brain or kidneys.

Radiographic and laboratory findings

Hematologic (CBC with differential): 

Anemia is common but the cause is usually multifactorial. The classic, but not the most common anemia is a hemolytic anemia.  This anemia is associated with increased reticulocyte count, positive direct Coombs test and low haptoglobin.  Anemia of chronic disease is the most common anemia seen in lupus patients.

Leukopenia is common but it is rare for the white blood cell count to be below 1000/µL. Lymphopenia is also common but neutropenia is rare.

Mild to profound thrombocytopenia can occur and can be associated with antiphospholipid antibodies.

The partial thromboplastin time may be prolonged due to the presence of a lupus anticoagulant.

The sedimentation and C-reactive protein level can be elevated.

The blood urea nitrogen and creatinine may be elevated from chronic kidney disease or renal failure.

Cholesterol may be elevated secondary to nephrotic syndrome.

Lupus nephritis may present as proteinuria alone or proteinuria with active urine sediment.  Hematuria can occur in association with these features but isolated hematuria is unlikely to be due to lupus nephritis and would prompt a search for other causes.

Special Tests:

Virtually all SLE patients have a positive antinuclear antibody test.  Some autoantibodies are very specific for lupus, such as anti-dsDNA antibodies (occurs in about 30% of patients with SLE) or anti-Smith antibodies.  Other autoantibodies such as anti-Ro/SSA, anti-La/SSB, and anti-ribonucleoprotein occur in SLE but can also be seen with other diseases.  Antiphospholipid antibodies are found in about 50% of SLE patients during the course of disease and are associated with an increased risk of thrombosis and pregnancy loss. 

Reduction in the complement components C3 and C4 or in total hemolytic complement occurs frequently but is not specific for lupus.

False positive syphilis serologies can be seen.

A skin biopsy with immunofluorescent staining for immunoglobulins and complement is helpful with diagnosing SLE cutaneous lesions.

A renal biopsy in patients with nephritis can determine the International Nephrology Society subtype and give information on both activity and chronicity.

In patients with neuropathy, a nerve conduction study and sural nerve biopsy may be needed to document vasculitis.

An electromyelogram and muscle biopsy should be considered in the evaluation of myositis.

Risk factors and prevention

Patients should avoid exposure to direct or reflected sunlight and other sources of ultraviolet light (e.g., fluorescent and halogen lights). They should use sunscreens, especially those that block both UV-A and UV-B, with a high skin protection factor (SPF) of 55 or greater.

Cigarette smoking may increase the risk of developing SLE, and smokers can have more active disease.  Patients should be counseled on smoking cessation and provided with help to do so.

Patients should be aware that lupus can flare during pregnancy and that they can be at increased risk for miscarriage.  Therefore, lupus patients should be advised to be evaluated and followed by a rheumatologist and a high risk obstetrician prior to conceiving. 

Treatment option

Table 2. Drugs used to manage SLE

NSAIDS

Useful for fever, headache, serositis, arthralgia/arthritis, and myalgia.

Antimalarials

Hydroxychloroquine is FDA approved for SLE and rheumatoid arthritis.
Has disease-modifying properties and is steroid sparing.
Retinal examinations should be performed annually.
Quinacrine or chloroquine can be added for resistant skin lesions.

Corticosteroids

Approved by the FDA for SLE.
Induction therapy for organ threatening disease is 1mg/kg/day of prednisone or intravenous equivalent for up to 4 to 6 weeks followed by tapering.  "Pulse" intravenous doses of methyprednisolone, in doses of 250- 500 mg daily to twice daily to 1 gm daily intravenously for 3-5 days, are sometimes given in acutely and seriously ill hospitalized patients.
Non-organ threatening disease responds to 0.25mg/kg/day or less.

Immunosuppressants

  1. Methotrexate: used for synovitis and some rashes
  2. Azathioprine: steroid sparing in patients with organ-threatening disease
  3. Cyclophosphamide: for nephritis and CNS vasculitis and helpful in selected patients with organ threatening manifestations.
  4. Mycophenolate mofetil: for nephritis
  5. Leflunomide: for synovitis
  6. Cyclosporine: may be useful for membranous nephritis, red cell hypoplasia and lupus urticaria.

Biologics

  1. Rituximab: for thrombocytopenia and some organ-threatening complications.
  2. Belimumab: FDA approved for SLE and used for non-organ threatening disease.


Outcomes

Poor prognostic factors for survival in SLE include:

  • Renal disease (especially diffuse proliferative glomerulonephritis)
  • Hypertension
  • Male gender
  • Young age
  • Older age at presentation
  • Poor socioeconomic status
  • Black race
  • Presence of antiphospholipid antibodies
  • Antiphospholipid syndrome
  • High overall disease activity

Lupus can be a life-threatening disease and 10% die within five years of diagnosis.  Life expectancy may be shortened.  Late mortality shows a disproportionate contribution from atherosclerotic disease.  However, the spectrum of severity of lupus is broad and with appropriate management, patients with lupus can live full and healthy lives. 

Holistic medicine

Dehydroepiandrosterone (DHEA): DHEA supplements, derived from wild yam, have been shown in randomized, controlled trials to modestly reduce the dose of steroids needed to stabilize symptoms in some people who have lupus.

Flaxseed:  Flaxseed contains a fatty acid called alpha-linolenic acid, which may decrease inflammation.  Though suggested by some authors to be of potential benefit in lupus nephritis, the strength of available evidence does not support this recommendation.   

Fish oil:  Fish oil supplements contain omega-3 fatty acids and some have suggested that the anti-inflammatory effects of fish oil could benefit patients in both reduction of disease symptoms and in reducing cardiovascular risk.  However, current evidence is inadequate to make definitive recommendations.

Vitamin D:  There is some evidence to suggest that people with lupus with low vitamin D levels may have higher disease activity and those with higher vitamin D levels have improved bone density levels. 

Miscellany

Neonatal lupus is a syndrome resulting from passively transferred autoimmunity that occurs in some babies born to lupus mothers with anti-Ro/SSA and/or anti-La/SSB antibodies.  The most serious complication of neonatal lupus is congenital heart block.  This occurs in 1-2 percent of such pregnancies and in about 15 percent of subsequent pregnancies in a mother who has given birth to a child with congenital heart block.

Key Terms

Autoimmune disease; lupus; systemic lupus erythematosus

Skills and competencies

Understand and define lupus and its clinical manifestations.

Correctly use laboratory studies and special studies to aid with the diagnosis of lupus.

Gain general concepts about the management of lupus.

Content

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