Epidemiology
- Prevalence in USA: 12-50 cases per 100,000 in urban areas
- Incidence: 1.8-7.6 cases per 100,000 per year
- Genetic Factors
- Higher concordance in monozygotic twins
- 10% frequency of disease with >1 family member affected
- 6% of cases have inherited deficiencies of complement copmponents
- Possible Viral Factors
- Increased incidence of anti-EBV Ab in children and adolescents with SLE
- Risk Factors
- Female Sex: 90% of cases occur in females (usually of child-bearing age)
- Estrogen enhances antibody response
- Black Race: 3-fold more common in blacks (vs whites)
- More severe disease is manifested in blacks (vs whites)
- HLA-DR2/HLA-DR3-Positive
- Complement Component Deficiencies (C1q, C4A, C4B, C2): in 6% of cases
- Complement-Related Regulatory Protein Haplotypes
- Mannose-Binding Lectin Haplotypes
- IgG Fc Receptor Haplotypes
- Female Sex: 90% of cases occur in females (usually of child-bearing age)
Etiology
Drug-induced SLE
- High-Risk
- Procainamide (see [[Procainamide]])
- Induces positive-ANA in 50-75%
- Causes SLE in 20% of treated patients
- Hydralazine (see [[Hydralazine]])
- Induces positive-ANA in 20-30%
- Causes SLE in 10% of treated patients
- Isoniazid (see [[Isoniazid]])
- Penicillamine (see [[Penicillamine]])
- Phenytoin (see [[Phenytoin]])
- Procainamide (see [[Procainamide]])
- Moderate-Low Risk
- Minocycline (see [[Minocycline]])
- Pyrazinamide
- Quinidine
- Chlorpromazine
- Carbamazepine (see [[Carbamazepine]])
- Oxacarbazepine
- Propafenone (see [[Propafenone]])
- Nitrofurantoin (see [[Nitrofurantoin]])
- Methyldopa
- Beta Blockers (see [[Beta Blockers]]): practolol, acebutolol, labetolol, pindolol, atenolol
- Ethosuximide
- Sulfasalazine (see [[Sulfasalazine]])
(Note: estrogen-containing oral contraceptives and ibuprofen are known to exacerbate SLE, but are probably not etiologies of drug-induced SLE)
Physiology
- SLE-Associated Vasculitis: hypersensitivity vasculitis (mostly involving the post-capillary venules within superficial dermis) with leukocytoclasis
- Probably due to immune complex deposition
- Abnormal humoral and cellular immune response
- B-cell hyperactivity and T-cell Dysfunction: antibody overproduction/ immune complex deposition (resultant PMN, then mononuclear cell infiltration)
- Steps in Pathogenesis
- Loss of tolerance to DNA and chromatin -> B-cells make ANA
- Immune amplification: -> B-cell and T-cell hyperactivity
- Specific end-organ damage
- Neuropsych Manifestations: may be related to anti-DNA Ab cross-reacting with brain NR-2 glutamate receptor
- Pattern of Antibody Development: about 78% of cases have ANA titer of >1:120 prior to diagnosis (anti-dsDNA was found in 55%)
- Chronic Interstitial Pneumonitis: probably due to immune complex deposition (by IF and EM: immune deposits in alveolar walls and capillaries)
- Immune complexes are not seen in Acute Lupus pneumonitis but some studies variably demonstrate these in diffuse alveolar hemorrhage
Diagnosis
CBC
- Anemia (iron deficiency) is usually present in DAH but not Lupus pneumonitis
- Leukocytosis
Serology
ANA
- ANA Assay: typically uses HEP-2 cells -> detects multiple cytoplasmic and nuclear antigens (DNA, histone proteins, and chromatin)
- Sensitivity for SLE: 90-95%
- Specificity for SLE: low
- Usually 1:160 is the cutoff titer for a significant positive ANA
- ANA may be positive (usually at low titer) with advancing age, other autoimmune diseaeses, viral infection, and chronic inflammation
- Anti-DNA (70%): associated with disease activity and nephritis
- Anti-dsDNA: targets double-stranded DNA
- Sensitivity for SLE: 50-75%
- Specificity for SLE: high
- In conjunction with low complement levels, anti-dsDNA is strongly associated with disease activity
- Anti-ssDNA (targets single-stranded DNA): not SLE-specific
- Anti-dsDNA: targets double-stranded DNA
- Anti-Sm: targets protein complexed to small nuclear RNA
- Sensitivity for SLE: 30%
- Specificity for SLE: high (most specific anitbody for SLE)
- Anti-Histone: targets histone proteins
- Sensitivity for Idiopathic SLE: 70%
- Sensitivity for Drug-Induced SLE: 95%
- Anti-Ro: targets RNA transcription factors
- Sensitivity for SLE: 30%
- Associated with renal disease
- Positive in 80% of Acute Lupus Pneumonitis cases (probably forms immune complexes, which are deposited in the lungs)
- Anti-La: targets RNA transcription factors
- Sensitivity for SLE: 10%
- Always associated with anti-Ro
- Associated with renal disease
- Anti-RNP: targets ribonucleoprotein complexed to U1RNA
- Sensitivity: 40%
- If present in SLE without anti-DNA< risk of renal disease is low
Anti-Phospholipid Antibodies
- Anti-Cardiolipin
- Positive in 50% of SLE cases
- Associated with increased risk of venous and arterial thrombosis, thromobcytopenia, valvular heart disease, and spontaneous abortion
- Associated with prolonged PTT and false-positive VDRL
- Lupus Anticoagulant
- Positive in 20-30% of SLE cases
- Assay: Russell Viper Venom or RBNP
- Associated with increased risk of thrombosis
Other Autoantibodies
- Anti-Neuronal: targets neuronal or lymphocyte surface antigens
- Sensitivity for SLE: 60%
- High CSF IgG titers are associated with diffuse CNS disease
- Anti-Erythrocte: targets erythrocyte surface antigens
- Sensitivity for SLE: 60%
- Small perecentage of these patients develop hemolysis
- Anti-Platelet: targets platelet surface antigens
- Sensitivity for SLE: unknown
- Anti-Lymphocyte: targets lymphocyte surface antigens
- Sensitivity for SLE: 70%
- Probably associated with leukopenia and abnormal T-cell function
- Rheumatoid Factor (RF)
- Sensitivity for SLE: 20%
- ANCA: negative
- Anti-GBM: negative
Protein C and S
- May be decreased (acquired deficiencies seen in SLE: may cause hypercoagulability)
Serum Complement
- Decreased
- In conjunction with presence of anti-dsDNA, low complement levels are strongly associated with disease activity
ESR
- Elevated
Bone X-Rays
- Minimal findings
Brain MRI
- May reveal subtle changes
Arthrocentesis
- Synovial WBC: >2000 (ranges from 50-50k) with 0-60% PMN
Renal Bx
- Focal segmental necrotizing GLN, crescents
Skin Bx
- Diagnostic in cases of vasculitis
Clinical Criteria: 1982 American College of Rheumatology
(need at least 4)
- Malar Rash (57%):
- Discoid Rash (18%): circular with erythematous rim over head, sun-exposed areas/only 5% of patients with isolated discoid LE progress to SLE
- Photosensitivity (43%)
- Oral/Nasopheryngeal ulcers (27%)
- Non-Erosive arthritis (86%): symmetric involving PIP/ MCP/ wrists/ knees
- Pleuritis (52%)/Pericarditis (17%)
- Proteinuria (50%)/ Urinary casts (36%)
- Seizures (12%)/Psychosis (13%): abnormal EEG in 70% of these cases
- Hemolytic Anemia (12%)/ Leukopenia (46%)/ Lymhophenia (40%)/ Thrombocytopenia (21%): See Pancytopenia
- LE cells (73%)/ Anti-DNA (67%)/ False-positive VDRL (15%)
- Positive ANA (99%)
Clinical Presentations
Pulmonary Manifestations
(occur in 38-89% of SLE cases)
Interstitial Lung Disease (Chronic Interstitial Lupus Pneumonitis) (see [[ILD-Etiology]])
- Epidemiology
- Diffuse lung disease occurs in anywhere from 4-70% of SLE cases (variability depends on diagnostic criteria used in studies)
- Only 3% of cases have diffuse lung disease at onset of SLE (and only 5% develop interstitial lung disease during follow-up)
- Mean Duration of SLE Prior to Interstitial Lung Disease Presentation: 9.6 years (range: 3-23 years)
- Mean Age at Presentation of Interstitial Lung Disease: 46 y/o
- Risk Factors for SLE-Associated Interstitial Lung Disease
- Increasing Age
- Pneumonitis
- Anti-RNP Antibodies
- Diagnosis
- ABG: hypoxemia
- PFT’s: restriction (43-49% of cases), decreased DLCO (72-80% of cases)
- CXR/Chest CT: CXR changes are seen in 30-50% of ILD cases
- Reticular or reticulonodular infiltrates (lower-lobe predominance) with decreased lung volumes: may mimic pattern seen in idiopathic pulmonary fibrosis
- Honeycombing: small cystic changes (seen best in lower fields) seen late in course
- Radiographic honeycombing correlates well with pathologic honeycombing
- OLB: usual interstitial pneumonia (UIP)-like pattern
- Enlarged peribronchiolar lymphoid follicles may be present: these are not typical of idiopathic pulmonary fibrosis
- Cellular histology is more common than fibrotic histology (even in autopsy studies)
- Honeycombing: may occur late in course
- Clinical: insidious dyspnea (similar to idiopathic pulmonary fibrosis), cough, pleuritic chest pain (note that this syptom is unusual in idiopathic pulmonayr fibrosis), basilar or diffuse dry crackles/cyanosis and clubbing are uncommon/cor pulmonale is rare
- Treatment: corticosteroids -> partial regression
Acute Lupus Pneumonitis (see [[Pneumonia]])
- Epidemiology: occurs in <2% of SLE cases
- Lupus pneumonitis is the initial presentation of SLE in 50% of cases
- Diagnosis
- ABG: hypoxemia
- CXR/Chest CT
- Basilar-predominant alveolar infiltrates: may be migratory, recurrent, and/or polymorphic
- HRCT: diffuse ground-glass infiltrates and/or consolidation, reticular infiltrates, honeycombing (mimics accelerated idiopathic pulmonary fibrosis)
- OLB (usually non-specific and variable): interstitial mononuclear cell infiltration (most common pattern)
- Diffuse alveolar damage may occur
- Clinical: probably precedes development of interstitial lung disease
- Fever
- Cough
- Dyspnea
- Acute Lung Injury-ARDS (see [[Acute Lung Injury-ARDS]])
- Treatment
- Corticosteroids + cytotoxics (cyclophosphamide)
- Plasmapheresis: has been used, in combination with steroids + cytotoxics to treat Acute Lupus Pneumonitis -> efficacy is not clear
- Cyclosporine A: may be used
- Prognosis
- Over 50% mortality rate once respiratory failure occurs
Pleuritis (see [[Pleural Effusion-Exudate]])
- Epidemiology: pleural disease is the most common pulmonary manifestation of SLE
- Effusion or pleuritic chest pain occurs in 50-75% of cases (67% have autopsy findings of pleuritis or effusion)
- Pleural effusion: occurs in about 40% of cases overall (normal and drug-induced SLE)
- Effusion and/or pleuritis is the presenting feature in 5% of cases
- 20% of cases have effusion at onset of systemic disease
- 50% have pleural involvement at some point during disease course
- 50-100% have pleural involvement by autopsy
- Effusion or pleuritic chest pain occurs in 50-75% of cases (67% have autopsy findings of pleuritis or effusion)
- Physiology: local immune pleuritis
- Diagnosis
- CXR/Chest CT: usually small-moderate bilateral effusions in 50% of cases (can be unilateral, massive in some cases)
- Hemopneumothorax and spontaneous hemothorax may occur in some cases (due to subpleural hemorrhage)
- Pleural Fluid Pattern
- Exudative
- Appearance: serous, turbid, or bloody
- Glucose: usually >60 mg/dL, with pH >7.35 (only 20% of cases have glucose <60 mg/dL and pH <7.3)
- LDH: usually <500 U/L (lower than in RA)
- Total protein:
- Cell Count/Cytology: several hundred-20k nucleated cells (can be either PMN, during pleurisy, or lymphocytic-predominant, during chronic phase)
- Pleural: Serum ANA Ratio >1.0 (with pleural ANA >1:160): may be diagnostically useful
- Pleural complement: decreased (also seen in RA)
- Pleural LE cells: diagnostic of SLE when present (less used today though)
- Pleural C3, C4, CH50: decreased
- Pleural immune complexes (DNA-anti-DNA): may be present
- Pleural lining cells: IF positive for anti-IgM, anti-IgG, or anti-C3
- CXR/Chest CT: usually small-moderate bilateral effusions in 50% of cases (can be unilateral, massive in some cases)
- Clinical (usually associated with flare of systemic symptoms): no difference in drug-induced cases
- Pleuritic Chest Pain (86-100%): may be recurrent and intractable in some cases
- Cough (65%)
- Dyspnea (50%)
- Pleural Rub (71%)
- Fever (57%)
Shrinking/Vanishing Lung Syndrome
- Physiology: due to diaphragmatic dysfunction (inspiratory and expiratory muscle weakness associated with myopathy) or an unspecified restriction in chest wall expansion
- Diagnosis
- PFT’s: restriction, decreased DLCO, decreased MIP/MEP/MVV
- CXR/Chest CT Pattern: low lung volumes
- Clinical: exertional dyspnea
- Treatment: usually self-limited (although occasionally severe)
- Corticosteroids + cytotoxics: may improve
Pulmonary Hypertension (see Pulmonary Hypertension, [[Pulmonary Hypertension]])
- Epidemiology
- Pulmonary hypertension with cor pulmonale occurs in <5% of cases (may complicate both Acute Lupus Pneumonitis and Chronic Interstitial Lupus Pneumonitis but uncommonly occurs without parenchymal disease)
- Pulmonary hypertension has been reported with increasing frequency
- Pathogenesis: probably due to vasoconstriction (rather than pulmonary vasculitis)
- Must rule out thromboembolism as etiologic (due to increased risk in SLE)
- Diagnosis
- Echo: subclinical pulmonary HTN is detected by Echo in 10% of SLE cases (usually in association with Raynaud’s)
- Clinical: in cases of pulmonary vasculitis without parenchymal disease, Raynaud’s is usually present
- Treatment:
- Corticosteroids + cytotoxics: may improve SLE-associated pulmonary hypertension
- Pulmonary vasodilators: flolan improves PVR and exercise capacity
- Prognosis: 2-year survival (in severe pulmonary hypertension) is <50%
Acute PE
- Epidemiology: 10% risk of thrombosis in absence of anti-phospholipid antibodies in SLE
- Physiology: due to hypercoaglable state
Anti-Phospholipid Antibody Syndrome (see [[Anti-Phospholipid Antibody Syndrome]])
- Epidemiology
- Higher risk of thrombosis (approximately 30%) in presence of anti-phospholipid antibodies in SLE
- Higher risk of impaired lung function in presence of anti-phospholipid antibodies in SLE
- Clinical: thromboembolism
Diffuse Alveolar Hemorrhage (see [[Diffuse Alveolar Hemorrhage]])
- Epidemiology: rarely occurs in SLE
- However, among the connective tissue diseases, diffuse alveolar hemorrhage is most commonly seen in SLE
- Diffuse alveolar hemorrhage is an uncommon initial presentation of SLE
- Autopsy studies confirm that this rarely is present in pulmonary hypertension patients
- Most patients with diffuse alveolar hemorrhage have concomitant nephritis
- Diagnosis
- ABG: hypoxemia
- PFT’s: increased DLCO during active alveolar hemorrhage
- CXR/Chest CT
- Alveolar infiltrates (during acute alveolar hemorrhage): predominantly basilar (may be migratory, recurrent, polymorphic)
- Interstitial infiltrates (following recurrent alveolar hemorrhage)
- FOB: may demonstrate hemorrhage
- BAL: hemosiderin-laden macrophages (appear a bout 48 hrs after onset of hemorrhage/hemosiderin score >100 suggests signifcant diffuse alveolar hemorrhage)
- OLB: granular tissue staining (IgG and C3) in alveolar interstitium (occasionally within walls of intra-alveolar blood vessels), immune complexes (by LM or EM) may be present, pulmonary capillaritis may or may not be present, intraalveolar RBC with hemosiderin-laden macrophages
- Clinical: hemoptysis (may be severe and associated with respiratory failure)
- Treatment: corticosteroids + cytotoxics (cyclophosphamide)
- Prognosis: 70% mortality (and usually recurrent in survivors)
- Death is usually due to hemorrhage, coexistent renal or CNS disease, or infection
Cricoarytenoid Arthritis (see [[Cricoarytenoid Arthritis]])
- Clinical: presents with globus sensation, sore throat, hoarseness, exertional dyspnea, otalgia, nocturnal or daytime stridor, dysphagia, odynophagia/ upper airway obstruction
Epiglottitis/Laryngitis/Vocal Cord Edema (see [[Epiglottitis]])
- Epidemiology: rarely occurs in SLE
Bronchiolitis Obliterans (see [[Bronchiolitis Obliterans]])
- Epidemiology: has been reported (usually steroid-responsive)
Cryptogenic Organizing Pneumonia (see [[Cryptogenic Organizing Pneumonia]])
- Epidemiology: rarely occurs in SLE -> few case reports
Lymphocytic Interstitial Pneumonia (see [[Lymphocytic Interstitial Pneumonia]])
- Epidemiology: few case reports in SLE
Acute Reversible Hypoxemia
- Epidemiology: reported in acutely ill, hospitalized cases (accompanied by diffusion abnormalities and elevated plasma complement split products)
Pulmonary Infection
- Epidemiology: 34x as common as Acute Lupus Pneumonitis (must always rule out infection first before instituting steroids + cytotoxics)
Atelectasis (see [[Atelectasis]])
- Epidemiology: may occur in absence of diaphragmatic dysfunction in some cases
Necrotizing Tracheitis
- Epidemiology: rarely occurs in SLE
Rheumatologic Manifestations
- Polyarthritis:
- Raynaud’s Phenomenon:
- Vasculitis (20%):
Dermatologic Involvement
- Alopecia (40%): correlates with disease activity
- Panniculitis (5%)
- Photosensitivity:
- Malar rash:
- Discoid lesions:
- Vasculitis: palpable purpura, nodules, ulcers
Renal Manifestations
- Glomerulonephritis
- Nephrotic syndrome (50%)
Cardiac Manifestations
- Coronary Artery Disease: SLE is major cardiac risk factor for coronary artery disease (like DM)
- Libman-Sacks endocarditis (10%)
- Myocarditis
- Pericarditis: cardiomegaly, pericardial effusion
GI Manifestations
- Oral ulcerations:
- Abnormal LFT’s (40%)
Neurologic Manifestations
- Neuropathy (15%)
- Phrenic Neuropathy with Acute/Chronic Hypoventilation (see Acute Hypoventilation, [[Acute Hypoventilation]] and Chronic Hypoventilation, [[Chronic Hypoventilation]])
- Myopathy (40%):
- Lupus cerebritis:
Heme Manifestations
- Anemia of chronic disease (70%):
- Splenomegaly (15%)
- Lymphadenopathy (20%)
- Thrombosis (15%): predisposed by Lupus anticoagulant, anticardiolipin Ab, or acquired protein C and S factor deficiencies
Ocular Manifestations
- Occur in 15% of cases
Other Manifestations
- Weight loss and fever (95%)
- Fatigue
- Anorexia
Clinical Manifestations of Drug-induced SLE
- Epidemiology
- Likely occurs in “slow acetylators”: those who metabolize these drugs abnormally
- Diagnosis
- All drug-induced cases are ANA-positive (usually anti-histone)
- Anti-dsDNA and hypocomplementemia are rarely present
- Complement: variable
- Coombs Test: positive in 33% of cases
- Elevated ESR
- Hypergammaglobulinemia
- CXR/Chest CT
- Pleural Effusions (33% of cases)
- Cardiomegaly (from pericardial effusion)
- Basilar Infiltrates
- Atelectasis
- Pleural Fluid: glucose is normal
- All drug-induced cases are ANA-positive (usually anti-histone)
- Clinical: usually insidious onset in patient who has been on the drug for months-years
- Polyarthralgia/Polyarthritis (25-50%)
- Myalgia
- Fever
- Pleurisy/Pleuropericarditis (30-50%)
- Cutaneous Lesions: common
- Nephritis and CNS involvement: uncommon
- Likely because complementis not usually involved with drug-induced SLE cases
Treatment
- NSAID’s: for arthritis, fever, mild serositis (useful for effusions)
- Antimalarials (Hydroxychloroquine): useful for skin disease/arthritis
- Corticosteroids (prednisone 1-2 mg/kg/day): for acute life-threatening systemic signs
- Effusion: dramatic response to steroids, resolving within 2 weeks (spontaneous resolution of SLE effusions does not occur)
- ILD: usually poor response (although 9/14 responded in one series)
- Acute Lupus Pneumonitis: usually responds to steroids + cytotoxics
- Cytotoxics: steroid-sparing/useful for renal disease
- Azathioprine: least toxic
- Cytoxan: most effective
- Proven benefit of 6 mo pulse solumedrol + pulse Cytoxan in proliferative nephritis (unknown effect on mortality though)
- Avoid use in pregnancy due to teratogenic risk and possible risk of fetal demise
- Chlorambucil:
- Mycophenolate Mofetil (Cellcept): proven benefit of steroids + mycophenolate (as compared to steroids + cyctoxan) in Chinese patient group with nephritis after 6 mo (but lower response after longer follow-up)
- Requires further study
- Auto-BMT: has been used in some cases
- Renal Transplantation: may be necessary
- Prasterone (androgen): may have some steroid-sparing effect
Treatment of Diffuse Alveolar Hemorrhage
- Corticosteroids + Cyclophosphamide (or Azathioprine): standard regimen
- Plasmapheresis: has been combined with steroids + cyclophosphamide, but probably has little efficacy
- Antibiotics: useful, as infection may be a trigger for alveolar hemorrhage
Treatment of Pulmonary Hypertension
- 2-year survival is 50% in severe disease
- Treat multiple mechanisms with some combination of anticoagulation, vasodilators, steroids + cytotoxics
Parameters to Follow with Therapy
- ESR
- Anti-dsDNA Titer
- CBC: Hct, leukocyte count, and platelt count
- Serum Complement
- RUA
- Creatinine
Treatment of Drug-Induced SLE
- Withdraw drug with or without corticosteroids -> usually good response
Treatment of Co-Existing Cardiac Disease
- Treat hyperlipidemia
- Administer ASA (80 mg/day): if not contraindicated
- Treat homocysteinemia (if present) with folate
- Minimize steroids, if possible
Prognosis
- 5-Year Survival: >90% (but mortality rate is 3-fold higher than that of the general population)
- Predictors of Mortality
- Poverty
- Degree of tissue damage
- Disease activity
- Cause of Death (over 5 year follow-up): mainly SLE and infection
References
- Drug-induced systemic lupus erythematosus. Clin Pharm. 1985 Nov-Dec;4(6):657-63
- Pulmonary hypertension in systemic lupus erythematosus: evaluation of clinical characteristics and response to immunosuppressive
treatment. J Rheumatol 2002;29:282–7 - Pulmonary hypertension in a lupus clinic: experience with twenty-four patients. J Rheumatol 1990;17:1292– 8
- Immunosuppressive therapy in lupus- and mixed connective tissue disease-associated pulmonary arterial hypertension: a retrospective analysis of twenty-three cases. Arthritis Rheum 2008;58:521–31
- Diffuse Alveolar Damage: Uncommon Manifestation of Pulmonary Involvement in Patients With Connective Tissue Diseases. Chest 2006; 130:553–558