Systemic Lupus Erythematosus (SLE)

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

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]])
  • 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-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
  • 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
  • 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

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
  • 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