para>Women with SLE have a 7- to 50-fold increased risk of coronary artery disease and may present with atypical/nonspecific symptoms. é á
EPIDEMIOLOGY
Predominant age: 15 to 45 years é á
Incidence
- Per year, 1.6 to 7.6/100,000 and increasing due to better diagnosis
- Most common: African American women (8.1 to 11.4/100,000/year)
- Least common: Caucasian men (0.3 to 0.9/100,000/year)
Prevalence
Occurs in 30 to 50/100,000 and increasing due to increased survival é á
ETIOLOGY AND PATHOPHYSIOLOGY
- Skin: photosensitivity; scaly erythematous, plaques with follicular plugging, dermal atrophy, and scarring; nonscarring erythematous psoriasiform/annular rash; alopecia; mucosal ulcers
- Musculoskeletal: nonerosive arthritis; ligament and tendon laxity, ulnar deviation, and swan neck deformities; avascular necrosis
- Renal: glomerulonephritis
- Pulmonary: pleuritis, pleural effusion, alveolar hemorrhage, pneumonitis, interstitial fibrosis, pulmonary hypertension, pulmonary embolism (PE)
- Cardiac: nonbacterial verrucous endocarditis, pericarditis, myocarditis, atherosclerosis
- CNS: thrombosis of small intracranial vessels é ▒ perivascular inflammation resulting in micro- or macroinfarcts é ▒ hemorrhage
- Peripheral nervous system: mononeuritis multiplex, peripheral neuropathy
- GI: pancreatitis, peritonitis, colitis
- Hematologic: hemolytic anemia, thrombocytopenia, leukopenia, lymphopenia
- Vascular: vasculitis, thromboembolism
- Most cases are idiopathic with possible environmental factors.
- Drug-induced lupus: hydralazine, D penicillamine, quinidine, procainamide, minocycline, isoniazid, etc
Genetics
- Identical twins: 24 " ô58% concordance
- Fraternal twins and siblings: 2 " ô5% concordance
- 8-fold risk if first-degree relative with SLE
- Major histocompatability complex associations: HLA-DR2, HLA-DR3
- Deficiency of early complement components, especially C1q, C1r/s, C2, and C4
- Immunoglobulin receptor polymorphisms: FC Ä │R2A,FC Ä │R3A, and others
- Polymorphism in genes associated with regulation of programmed cell death, protein tyrosine kinases, and interferon production
RISK FACTORS
- Race: African Americans, Hispanics, Asians, and Native Americans
- Predominant sex: females > males (8:1)
- Environmental: UV light, infectious agents, stress, diet, drugs, hormones, vitamin D deficiency, and tobacco
COMMONLY ASSOCIATED CONDITIONS
- Overlap syndromes: rheumatoid arthritis (RA), Sj â Âgren syndrome, scleroderma
- Antiphospholipid syndrome; coronary artery disease; nephritis; depression
DIAGNOSIS
Consider SLE in multisystem disease including fever, fatigue, and signs of inflammation. é á
HISTORY
- Fever, fatigue, malaise, weight loss, headache
- Rash (butterfly/hyperpigmented ears or scalp), photosensitivity, alopecia
- Oral/nasal ulcers (usually painless)
- Arthritis, arthralgia, myalgia, weakness
- Pleuritic chest pain, cough, dyspnea, hemoptysis
- Early stroke (age <50 years), seizure, psychosis, cognitive deficits
- Proteinuria, cellular casts
- Hemolytic anemia, leukopenia, lymphopenia, thrombocytopenia
- Abdominal pain, anorexia, nausea, vomiting
- Raynaud phenomenon
PHYSICAL EXAM
- Vital signs: fever, hypertension
- Malar, discoid, psoriasiform, or annular rash, alopecia
- Oral/nasal ulcers (often minimally symptomatic)
- Lymphadenopathy, splenomegaly
- Acrocyanosis
- Inflammatory arthritis, tenosynovitis
- Pleural/pericardial rub, heart murmur
- Bibasilar rales
- Cranial/peripheral neuropathies
DIFFERENTIAL DIAGNOSIS
Undifferentiated connective tissue disease, Sj â Âgren syndrome, fibromyalgia, RA, vasculitis, idiopathic thrombocytopenia purpura, antiphospholipid antibody syndrome, drug-induced lupus é á
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
- Antinuclear antibody (ANA)
- High sensitivity (98%), low specificity
- False-positive rate of 5 " ô30%: elderly, autoimmune thyroid/liver disease, chronic infection, etc
- Low titers <1:160 of limited clinical use
- Anti " ôdouble-stranded DNA (dsDNA) and anti-Smith antibodies: high specificity for SLE; predictor of nephritis and hemolytic anemia
- Correlates with disease activity
- RNA protein antibodies (anti-RNP, anti-Ro, anti-La): less specific for SLE
- False-positive Venereal Disease Research Laboratory (VDRL) test: high sensitivity, low specificity. Surrogate marker of cardiolipin antibody presence
- Low serum complement levels: C3, C4
- Erythrocyte sediment rate (ESR): nonspecific, often high in active disease
- CBC: hemolytic anemia, thrombocytopenia, leukopenia, or lymphopenia
- Serum creatinine: elevated in lupus nephritis
- Urinalysis (UA): proteinuria, hematuria, cellular cast
- Phospholipid antibodies: cardiolipin immunoglobulin (Ig) G/IgM, lupus anticoagulant, Ä ▓2-glycoprotein IgG/IgM
- Anti-P (ribosomal autoantibodies) is associated with SLE arthritis and disease activity.
- Initial imaging is dependent on presenting symptoms.
- Radiograph of involved joints
- Chest x-ray: infiltrates, pleural effusion, low lung volumes
- Chest CT scan, ventilation-perfusion (V-Q) scan, duplex ultrasound for PE or deep vein thrombosis
- Head CT scan: ischemia, infarct, hemorrhage
- Brain MRI: focal areas of increased signal intensity
- Echocardiogram: pericardial effusion, valvular vegetations, pulmonary hypertension
- Contrast angiography for medium-size artery vasculitis: mesenteric/limb ischemia, CNS symptom
Follow-Up Tests & Special Considerations
- Hemolytic anemia: elevated reticulocyte count and indirect bilirubin, low haptoglobin, positive direct Coombs test
- Confirm positive phospholipid antibodies results in 12 weeks.
- If phospholipid antibodies are initially negative, but symptoms arise, repeat, as they may become positive over time.
- 24-hour urine collection/spot protein/creatinine to quantify proteinuria
- Histone antibodies present in >95% of drug-induced lupus (vs. 80% of idiopathic SLE)
- Fasting lipid panel and glucose
- Follow vitamin D[25(O)H] levels and replenish PRN.
Diagnostic Procedures/Other
- Renal biopsy to diagnose lupus nephritis (if UA abnormal)
- Skin biopsy with immunofluorescence on involved and uninvolved non " ôsun-exposed skin (lupus band test) may help differentiate SLE rash from others.
- Lumbar puncture in patients with fever and CNS/meningeal symptoms
- EEG for seizures/global CNS dysfunction
- Neuropsychiatric testing for cognitive impairment
- EMG/nerve conduction study (NCS) for peripheral neuropathy and myositis
- Nerve and/or muscle biopsy
- ECG, cardiac enzymes, stress tests
- American College of Rheumatology classification (not diagnostic) criteria: any 4 of the 11 listed (95% specificity and 85% sensitivity):
- Malar (butterfly) rash
- Discoid rash
- Photosensitivity: by patient history/physician observation
- Oral/nasopharyngeal ulcers
- Nonerosive arthritis: involving ≥2 peripheral joints
- Pleuritis OR pericarditis
- Renal disorder: proteinuria (>0.5 g/day or >3+) OR cellular casts (red cell, hemoglobin, granular, tubular, or mixed)
- Neurologic disorder: psychosis/seizures
- Hematologic disorder: hemolytic anemia, leukopenia (<4,000/mm3 on ≥2 tests), lymphopenia (<1,500/mm3 on ≥2 tests), thrombocytopenia (<100,000/mm3)
- Immunologic disorder: anti-DNA, anti-Sm, anticardiolipin IgG/IgM, lupus anticoagulant, or false " ôpositive VDRL findings
- Positive ANA in absence of drugs known to cause positive ANA
Test Interpretation
- Skin: vascular/perivascular inflammation, immune-complex deposition at dermal " ôepidermal junction, mucinosis, basal layer vacuolar changes
- Similar findings seen in other connective tissue disorders such as dermatomyositis
- Renal: mesangial hypercellularity/matrix expansion, subendothelial/subepithelial immune deposits, glomerular sclerosis, fibrous crescents
- Vary depending on degree of involvement
- Vascular: immune-complex deposition in vessel walls with fibrinoid necrosis and perivascular mononuclear cell infiltrates, intraluminal fibrin thrombi
TREATMENT
GENERAL MEASURES
- Education, counseling, and support
- Influenza/pneumococcal vaccines are safe; avoid live vaccines in immunocompromised patients.
- Low-estrogen oral contraceptives safe in mild SLE
MEDICATION
First Line
- Antimalarial agents and NSAIDs are first-line therapy for patients with mild SLE (1)[A].
- Hydroxychloroquine for constitutional and musculoskeletal symptoms, rash, mild serositis; may reduce flares and increase long-term survival (2,3)[A]. NSAIDs for musculoskeletal manifestations, mild serositis, headache, and fever (2)[C]
- Systemic glucocorticoids (prednisone or equivalent)
- Low dose (<0.5 mg/kg) for minor disease activity not responsive to NSAIDs or when NSAIDs are contraindicated (2)[A]
- High-dose (1 to 2 mg/kg/day) (2)[A] or IV pulse methylprednisolone for organ-threatening disease, particularly CNS and renal; often combined with immunosuppressive agent (2)[A]
- Topical glucocorticosteroids for skin manifestations
Second Line
- Belimumab as adjunct for preventing flares in patients with active lupus despite 1st-line therapy (4)[A]
- 10 mg/kg IV every 2 weeks â Ś 3 doses, then monthly
- Methotrexate (2)[A], azathioprine (2)[B], mycophenolate mofetil (2)[C], or leflunomide as steroid-sparing agent for persistent active disease or to maintain remission
- Requires laboratory monitoring for toxicity
- Treatments under investigation: rituximab, epratuzumab, abatacept, interferon-α inhibitors
- Immunosuppressive agents for severe disease
- Cyclophosphamide (2)[A]: adequate hydration to reduce risk of hemorrhagic cystitis
- Mycophenolate mofetil (2)[A]: more efficacious for lupus nephritis (1)[A]
SURGERY/OTHER PROCEDURES
Renal transplant for end-stage renal disease é á
COMPLEMENTARY & ALTERNATIVE MEDICINE
Biofeedback, visual imagery, cognitive therapy é á
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
- Difficult to differentiate SLE flare from infection; may need to treat both pending full evaluation
- IV pulse Solu-Medrol 1 g/day for 3 to 5 days for life- or organ-threatening disease (2)[A]
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
- Clinical evaluation for signs and symptoms
- Weekly to monthly for active disease
- Every 3 to 6 months for mild/inactive disease
- Measures of disease activity and damage: Systemic Lupus Erythematosus Disease Activity Index, British Isles Lupus Assessment Group Index, European Consensus Lupus Activity Measure
- Laboratory studies
- CBC with differential
- Serum creatinine, UA
- Vitamin D
- Declining C3/C4 and rising DS-DNA and ESR may correlate with disease activity.
- Monitor for adverse effects of treatment
- NSAIDs: GI bleeding and/or ulceration
- Glucocorticoids: glucose, lipids, bone density
- Hydroxychloroquine: ophthalmologic exam every 6 to 12 months
- Methotrexate: CBC, creatinine, albumin, aspartate aminotransferase (AST), alanine aminotransferase (ALT) every 2 months
- Azathioprine and mycophenolate mofetil: CBC every 1 to 3 months
- Cyclophosphamide
- CBC, creatinine, UA every 2 weeks, and liver function tests monthly during treatment
- UA every 6 to 12 months for life
DIET
- No special diet unless for complications such as renal failure, diabetes, hyperlipidemia (2)[C]
- Adequate calcium/vitamin D intake in patients on corticosteroids (2)[A]
- Low glycemic index or calorie-restricted diet in patients on corticosteroids
PATIENT EDUCATION
- Avoid UV light exposure: sunscreens (SPF ≥30), protective clothing (2)[B]
- Weight control, smoking cessation, exercise (2)[C]
- Stress avoidance/management
PROGNOSIS
- Permanent treatment-free remission is uncommon.
- 5-year survival after diagnosis is 95%.
- Poor prognostic factor: major organ involvement
- Drug-induced lupus resolves within weeks to months after discontinuation of the offending drug.
COMPLICATIONS
Infections, neoplasms, cardiac disease, nephritis, neuropsychiatric lupus; depression é á
Pregnancy Considerations
Exacerbations during pregnancy are less common when in remission for 6 months prior to conception.
Fetal loss is increased, especially in those with active lupus/antiphospholipid antibodies.
A 2% risk of congenital heart block if anti-SS-A (Ro) or anti-SS-B (La) antibodies are present.
See "Antiphospholipid Antibody Syndrome " Ł for recommendations regarding use of aspirin and heparin to prevent pregnancy complications.
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REFERENCES
11 Yildirim-Toruner é áC, Diamond é áB. Current and novel therapeutics in the treatment of systemic lupus erythematosus. J Allergy Clin Immunol. 2011;127(2):303 " ô312.22 Bertsias é áG, Ioannidis é áJP, Boletis é áJ, et al. EULAR recommendations for the management of systemic lupus erythematosus. Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics. Ann Rheum Dis. 2008;67(2):195 " ô205.33 Ruiz-Irastorza é áG, Ramos-Casals é áM, Brito-Zeron é áP, et al. Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review. Ann Rheum Dis. 2010;69(1):20 " ô28.44 Navarra é áSV, Guzm â ín é áRM, Gallacher é áAE, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet. 2011;377(9767):721 " ô731.
ADDITIONAL READING
Lisnevskaia é áL, Murphy é áG, Isenberg é áD. Systemic lupus erythematosus. Lancet. 2014;384(9957):1878 " ô1888. é á
SEE ALSO
Antiphospholipid Antibody Syndrome é á
CODES
ICD10
- M32.9 Systemic lupus erythematosus, unspecified
- M32.10 Systemic lupus erythematosus, organ or system involv unsp
- M32.14 Glomerular disease in systemic lupus erythematosus
- M32.19 Oth organ or system involv in systemic lupus erythematosus
- M32.11 Endocarditis in systemic lupus erythematosus
- M32.13 Lung involvement in systemic lupus erythematosus
- M32.15 Tubulo-interstitial neuropath in sys lupus erythematosus
- M32.12 Pericarditis in systemic lupus erythematosus
- M32.8 Other forms of systemic lupus erythematosus
ICD9
710.0 Systemic lupus erythematosus é á
SNOMED
- 55464009 Systemic lupus erythematosus (disorder)
- 239887007 systemic lupus erythematosus with organ/system involvement (disorder)
- 295101000119105 Nephropathy co-occurrent and due to systemic lupus erythematosus (disorder)
- 239890001 Systemic lupus erythematosus with multisystem involvement (disorder)
- 95332009 rash of systemic lupus erythematosus (disorder)
- 95408003 Systemic lupus erythematosus arthritis (disorder)
- 196138005 Lung disease with systemic lupus erythematosus (disorder)
- 309762007 Systemic lupus erythematosus with pericarditis
- 95644001 Systemic lupus erythematosus encephalitis
CLINICAL PEARLS
- Aggressiveness of therapy should reflect intensity of disease.
- Most important diagnostic test is the UA: if abnormal, order kidney biopsy; serum and urine lab values often do not reveal extent of kidney disease.
- Atherosclerotic and atheroembolic complications are the major cause of death; address modifiable cardiovascular risk factors.