Systemic lupus Erythematosus:
Is a chronic inflammatory disease characterized by autoantibodies directed against self antigens, leading to inflammatory damage of many target organs including the joints, kidneys, blood-forming cells, and the CNS.
•Prevalence rates: 4-250/100,000; increased among Native Americans, Asians, Polynesians, Hispanics, and African-Americans.
•Frequently affects women (ratio 4 : 1 before puberty to 8 : 1 afterward).
•Can occur at any age, most common age at onset = 15-40. Disease onset before 8 yr of age is unusual.
•The cause and disease mechanisms remain unknown.
•The hallmark of lupus is autoantibody production against many self antigens.
•Autoantibodies (ANA, anti-dsDNA, anti-Ro, anti-La, anti-Sm, anti-RNP, antiphospholipid antibody) may precede the onset of SLE by 9 yr, suggesting a presymptomatic state of autoimmunity.
Factors potentially trigger immune dysregulation including:
1.Genetic predisposition: is suggested by the high frequency (≈10%) in family members of ANA, hypergammaglobulinemia, and lupus or other autoimmune diseases.
Certain HLA types (HLA-B8, HLA-DR2, and HLA-DR3) occur with increased frequency among patients with lupus.
Congenital complement deficiencies (including C1q, C2, and C4 deficiency) also predispose to SLE.
2.Hormones:
One study of postpubertal boys and girls with lupus found higher follicle-stimulating hormone and luteinizing hormone levels and lower free androgen levels. Nonetheless, estrogen-containing contraceptives do not produce flares of SLE.
3.Environment:
Exposure to ultraviolet rays in sunlight exacerbates lupus manifestations.
•Children with lupus present with diverse and often severe manifestations.
•Children most frequently present with fever, fatigue, hematologic abnormalities, arthralgia or arthritis, rash, and renal disease.
•Symptoms may be intermittent or persistent.
Constitutional symptoms :
Fatigue.
Anorexia.
Weight loss.
Prolonged fever.
Lymphadenopathy.
Cutaneous manifestations (70%):
The characteristic malar or butterfly rash.
Rashes may be photosensitive and extend to all sun-exposed areas.
Other cutaneous manifestations include vasculitic-appearing erythematous macular eruptions (particularly on fingers, palms, and soles), discoid lesions, purpura, livedo reticularis, and Raynaud phenomenon.
Less common findings include sub-acute psoriasiform or annular skin lesions, bullous or urticarial lesions, and alopecia.
The characteristic butterfly rash in a patient with SLE.
Photosensitivity
Livedo reticularis. Lacelike bluish, purplish, or erythematous discoloration of the skin indicating vascular instability.
Discoid rash :
unusual in childhood
Raynaud phenomenon:
SLE vasculitis
SLE, Digital Vasculitis
Mucous membrane changes ranging from vasculitic erythema to ulcers occur, particularly on palatal and nasal mucosa.
Musculoskeletal findings (90%) include :
Arthralgia.
Arthritis.
Tendinitis.
Myositis.
Deforming arthritis is unusual, although hand arthritis can lead to ligament damage and severely lax joints.
Osteonecrosis of bone is common and presumed to be secondary to vasculopathy or corticosteroid treatment.
Renal manifestations (about 50%):
Glomerulonephritis.
Hypertension.
Nephrotic syndrome.
Renal failure.
Serositis :
Can affect pleural, pericardial, and peritoneal surfaces.
Hepatosplenomegaly and lymphadenopathy are often found.
Gastrointestinal manifestations most often resulting from vasculitis, include pain, diarrhea, melena, infarction, inflammatory bowel disease, and hepatitis.
Cardiac involvement may include valvular thickening and verrucous endocarditis, cardiomegaly, myocarditis, conduction abnormalities, heart failure, and coronary artery vasculitis and thrombosis.
Pulmonary manifestations include acute pulmonary hemorrhage, pulmonary infiltrates, and chronic fibrosis.
Early cardiopulmonary disease is often clinically silent and may be detected by annual ECHO and pulmonary function tests with diffusing capacities.
Neurologic manifestations :
Seizures.
Psychosis.
Stroke.
Cerebral venous thrombosis.
Pseudotumor cerebri.
Aseptic meningitis.
Chorea.
Global cognitive deficits.
Mood disorders.
Transverse myelitis.
Peripheral neuritis.
Antiphospholipid antibody syndrome:
Suggested by the occurrence of arterial or venous thrombosis that can occur in the brain or any organ, and associated with recurrent fetal loss, livedo reticularis, thrombocytopenia, and Raynaud phenomenon.
Thrombotic events can also be associated with the presence of lupus anticoagulant and acquired, activated protein C resistance.
A 12 yr old girl with SLE and antiphospholipid antibodies with painful cutaneous vasculitis of the right foot. Arterial thrombosis documented by angiography resulted in cyanosis of the large toe. Symptoms resolved with treatment with heparin and corticosteroids.
Patient with SLE developed digital infarcts during a flare of disease activity.
Anemia (Coombs-positive hemolytic anemia,
anemia of chronic disease).
Thrombocytopenia.
Leukopenia.
Elevated ESR and CRP.
Hypocomplementemia (decreased C3 or C4): correlates with disease activity.
Positive ANA and anti-double-stranded DNA antibodies.
Antinuclear antibody ANA:
During the course of SLE, more than 95% of patients will have an elevated ANA titer.
Although several patients will have negative ANA titers early in disease, repeated negative tests suggest that the diagnosis is not SLE.
The presence of ANA without clinical symptoms should not be considered diagnostic for SLE, although such persons are at increased risk.
ANA is the most sensitive screening test for SLE.
Anti-Smith:
is an immunoglobulin specific against Sm, a ribonucleoprotein found in the cell nucleus.
Not found in any other diseases, only in SLE. However, only 30% of patients with SLE have a positive test.
A positive test - usually means that lupus is present.
Most people with lupus have either anti-DNA or anti-Sm antibodies.
Anti-Smith is the most specific test for SLE.
Anti-dsDNA:
It is increased in SLE & is highly specific to SLE.
60-80% of patients with active SLE have a positive test.
Anti-ds-DNA antibody is not found in drug-induced lupus.
Titers of anti-ds-DNA correlate well with disease activity and with occurrence of glomerulonephritis.
A positive test in a person with lupus symptoms almost always means that lupus is present. However, the test can also be positive in some patients with rare diseases.
•Other antibodies to proteins in the nuclei
Anti-Ro, anti-La :
Anti-Ro is highly associated with photosensitivity; both are associated with neonatal lupus.
Approx. one quarter of pregnant women who have this antibody, will have a child who develops neonatal lupus.
If both tests are negative, the child of a pregnant woman will not develop neonatal lupus.
Anti-RNP:
If present with antibodies to DNA, then diagnosis is SLE.
If present alone, then diagnosis is mixed connective tissue disease.
Anti-Cardiolipin (Antiphospholipid) antibody:
Found in approx 33% lupus patients & have been associated with an incresased incidence of the development of secondary Antiphospholipid antibody syndrome.
Can be also increased in other diseases such as: some connective tissue diseases, Primary Antiphospholipid Antibody Syndrome and in patients with acute and chronic infections.
SLE should be considered in patients with multiorgan symptoms, especially if there are hematologic or urinalysis abnormalities.
The presence of 4 of 11 criteria serially or simultaneously strongly suggests the diagnosis.
Patients suspected to have lupus who demonstrate fewer than 4 criteria should receive appropriate medical treatment.
Renal biopsy is useful to confirm the diagnosis of lupus nephritis and to guide treatment.
The differential diagnosis depends on the presenting affected organ and includes:
Systemic-onset juvenile rheumatoid arthritis.
Acute poststreptococcal glomerulonephritis.
Acute rheumatic fever.
Infective endocarditis.
Leukemia.
Immune thrombocytopenic purpura.
Idiopathic hemolytic anemia.
Drug-Induced Lupus.
vDrug-Induced Lupus Erythematosus:
Is a syndrome that resembles SLE and is associated with symptoms such as fever, malaise, arthritis, serositis, and rash.
Has a less severe and less dramatic clinical presentation than SLE.
Occurs as a result of a hypersensitivity reaction with certain medications and biologic agents.
Rarely involves the kidneys or brain.
Usually resolves within weeks or months after discontinuation of the offending medication.
The treatment regimen depends on the affected target organs and disease severity.
Sun exposure should be minimized and include use of a sunscreen.
Patients are treated to promote clinical well-being, using serologic markers of disease activity as guidelines, including serum complement levels.
NSAIs used to treat arthralgia and arthritis.
Hydroxychloroquine: is often used to treat mild manifestations including skin lesions, fatigue, arthritis, and arthralgia, it may also reduce the risk of thromboembolic disease and lowers lipid levels.
Anticoagulant medications: are used in patients with thrombosis and antiphospholipid antibodies or a lupus anticoagulant. The length of therapy should be at least until lupus is in remission. Low molecular weight heparin is the anticoagulant of choice; warfarin can also be used (contraindicated in pregnancy).
Corticosteroids: control symptoms and autoantibody production, treatment with corticosteroids has improved kidney disease and the rate of survival.
Patients with SLE are often started on 1-2 mg/kg/24 hr of oral prednisone in divided daily doses. When complement levels increase to within the normal range, the dose is carefully tapered to the lowest effective dose.
Severely ill patients may require pulse intravenous corticosteroid therapy (30 mg/kg/dose, maximum 1 g/day, given over 60 min, for 3 days).
Patients with severe disease may require cytotoxic therapy.
Pulse intravenous cyclophosphamide has maintained renal function and prevented progression in patients with lupus nephritis, particularly diffuse proliferative glomerulonephritis, it is also used to treat vasculitis, pulmonary hemorrhage, and CNS involvement.
Azathioprine has been used to prevent renal disease progression.
Methotrexate, cyclosporine, and mycophenolate mofetil are used as steroid-sparing agents.
Autologous stem cell and allogeneic bone marrow transplantation for patients with severe, persistent disease are undergoing clinical trials.
Biologic agents that target cytokine production, in particular, anti-CD20/22 monoclonal antibodies, are also being studied.
Other potential therapies include rituximab (anti-CD20 monoclonal antibody), as well as blockade of interleukin 6, T cell co-stimulatory molecules and BlyS, a B-cell activating factor.
The extent of renal involvement may be out of proportion to findings on urinalysis; renal biopsy for staging can help determine whether an immunosuppressive agent such as cyclophosphamide needs to be added to a corticosteroid regimen.
The most important aspect of management of lupus is meticulous and frequent re-evaluation of clinical signs and laboratory data, especially for renal and serologic flares of disease.
Prompt recognition and treatment of disease flare is essential to patient outcome.
Lupus is a lifelong illness, and patients require monitoring indefinitely.
The major causes of death in patients with SLE currently include infection, nephritis, CNS disease, pulmonary hemorrhage, and myocardial infarction.
Untreated lupus may be followed by spontaneous remission, years of smoldering disease, or rapid death.
The 5-yr survival rate is >90%.
•Neonatal Lupus
Results from maternal transfer of IgG ayto-antibodies (usually anti-Ro or anti-La) between the 12th and 16th wk of gestation.
Only a small percentage of offspring of mothers with autoantibodies develop disease.
Symptoms usually derive from a single organ, although multiple organ involvement may occur and include congenital heart block, cutaneous lesions, hepatitis, thrombocytopenia, neutropenia, and pulmonary and neurologic disease.
Cutaneous lesions occur after ultraviolet exposure at about 6 wk of life and last 3-4 mo.
The rash most frequently occurs on the face and scalp, and 25% of rashes scar.
Treatment is supportive, most manifestations resolve, although congenital heart block is permanent and often requires cardiac pacing, either after birth or, when detected.
Corticosteroid treatment of the pregnant mother after heart block is detected early in utero and postnatal steroids may be effective.
Cardiomyopathy is a rare serious sequela, sometimes requiring heart transplantation.
Neonatal lupus must be distinguished from neonatal onset multisystem inflammatory disease (a rare syndrome characterized by fever, rash, arthropathy, chronic meningitis, seizures, uveitis, and lymphadenopathy, this autoinflammatory syndrome, resulting from defective IL-1 regulation in the innate immune system, is difficult to treat and requires long-term immunomodulation. Anakinra, an IL-1 antagonist, has been very successful in the treatment of a small cohort of these patients.
This healthy 6-week-old boy developed annular plaques on the chest, abdomen, and back several weeks earlier. He was otherwise well with normal complete blood count, liver function tests, but positive Ro and La antibodies typical of neonatal lupus. His mother had a history of arthralgias, fevers, and post partum deep venous thromboses.
This infant developed asymptomatic scaly red patches with dyspigmentation and subtle atrophy 3 months ago at the beginning of the summer. Serology demonstrated a positive ANA and anti-RNP. Her mother had a history of SLE.
Prepared by Dr. Nivin Hafiri
2007
