Systemic Lupus Erythematosus

Epidemiology and Etiology

Epidemiology

• Prevalence in the United States:
  • Overall: 20–150 per 100,000
  • Women: 100–400 per 100,000
  • Pediatric systemic lupus erythematosus (SLE): approximately 2.5 per 100,000
• More prevalent in people of African American or Asian descent
• More common in urban areas
• 10 times more common in women than men (no gender preference in drug-induced lupus)
• Peak age at onset: 
  • Adults: 18–55 years
  • Children: 9–15 years

Etiology

• The exact etiology is unknown.
• Predisposing factors:
  • Genetic:
    • HLA-DR2
    • HLA-DR3
    • Congenital deficiencies of complement factors C1q, C2, and C4
  • Hormonal:
    • Increased estrogen (e.g., oral contraceptives, hormonal replacement)
    • Decreased testosterone
    • Hyperprolactinemia
    • Thyroid abnormalities
  • Environmental:
    • Cigarette smoking
    • EBV exposure
    • Ultraviolet (UV) light exposure
    • Silica exposure
  • Drug induced

Pathophysiology

The exact mechanism is unknown. Patients likely have a genetic predisposition to autoreactive immune cells (B and T cells).

• Cell damage due to an environmental trigger → defective apoptosis and clearance of cellular debris → ↑ exposure to nuclear antigens (DNA and RNA from damaged cells)
• Autoreactive T and B cells are activated → production of autoantibodies:
  • ANA
  • Anti-double-stranded DNA (anti-dsDNA) antibodies
  • Anti-Smith (anti-Sm) antibodies
  • Anti-histone antibodies
  • Anti-Ro and anti-La antibodies
  • Anti-ribonucleoprotein antibodies
  • Antiphospholipid antibodies
• Antibody-antigen immune complexes form → endocytosis by B cells and dendritic cells 
  • B cells: activation of Toll-like receptors in endosomes → immune complexes are broken down by proteases → resulting peptides presented to T cells → T cell activation → further B cell activation
  • Dendritic cells: release of interferon → further B cell activation
• Perpetual T and B cell activation results in persistent ↑ in antibody levels
• Antibodies cause organ damage through: 
  • Immune (antigen-antibody)-complex deposition in microvasculature → excessive complement activation → inflammation
  • Immune-complex deposition in the basement membrane of organs (e.g., skin, kidneys)
  • Direct interaction with nuclear antigens on cell surfaces → complement activation → cell injury and apoptosis

Clinical Presentation

The clinical presentation of SLE is highly variable and can include several organ systems.

General

• Fatigue (most common symptom)
• Fever
• Weakness
• Weight loss
• Lymphadenopathy

Musculoskeletal

• 80%‒90% of cases
• Arthritis: 
  • Migratory
  • Symmetrical
  • Polyarticular
  • Nondestructive
  • Common locations: 
    • Knees
    • Hands
    • Fingers
• Joint deformities (rare):
  • Swan-neck deformity
    • Proximal interphalangeal joint hyperextension 
    • Distal interphalangeal flexion
  • Ulnar drift
  • Due to joint laxity 
• Arthralgia
• Myalgia

Mucocutaneous

• > 50% of cases 
• Photosensitivity
• Acute cutaneous lupus erythematosus:
  • A rash may precede systemic symptoms from months to years.
  • Localized:
    • Malar rash (“butterfly rash”)
    • Red or purple erythema on the cheeks and nasal bridge
    • Spares the nasolabial folds
    • Appears after sun exposure
  • Generalized:
    • Erythematous maculopapular lesions
    • Seen on sun-exposed skin
    • Common sites: extensor surfaces of arms, hands
    • Sparing of the knuckles may be noted.
• Discoid rash: 
  • Vibrant, scaling papules
  • Tends to cause scarring
• Non-scarring alopecia 
• Painless oral or nasal ulcers

Systemic manifestations

• Renal (> 50% of cases):
  • Lupus nephritis (of varying severity)
    • Asymptomatic proteinuria or hematuria
    • Nephrotic syndrome
    • Rapidly progressive glomerulonephritis
  • Hypertension
• Cardiac:
  • Pericardial effusion
  • Pericarditis
  • Libman-Sacks endocarditis
  • Severe myocarditis
  • Coronary artery disease
• Vascular:
  • Raynaud’s phenomenon
  • Thromboembolism
  • Vasculitis 
• Neuropsychiatric:
  • Headaches
  • Seizures
  • Neuropathies
    • Peripheral neuropathy
    • Cranial neuropathy
    • Autonomic neuropathy
    • Mononeuritis multiplex
  • Ischemic stroke
  • Aseptic meningitis
  • Demyelinating syndromes
    • Optic neuritis
    • Myelitis
  • Psychosis 
  • Anxiety
  • Depression 
  • Cognitive dysfunction
• Pulmonary:
  • Pleuritis
  • Pleural effusion
  • Chest pain
  • Pulmonary hypertension
  • Interstitial lung disease
    • Nonspecific interstitial pneumonia
    • Usual interstitial pneumonia
  • Diffuse alveolar hemorrhage
  • Shrinking lung syndrome (rare)
    • Progressive dyspnea
    • Diaphragm elevation
    • Decreased lung volumes
    • Restrictive pattern on pulmonary function test
• GI (40% of cases):
  • Esophagitis
  • Protein-losing enteropathy
  • Hepatitis
  • Splenomegaly
  • Acute pancreatitis
  • Mesenteric vasculitis
• Hematological:
  • Leukopenia (> 50% of cases)
  • Anemia
    • Iron-deficiency anemia
    • Autoimmune hemolytic anemia
  • Thrombocytopenia

Subtypes

Drug-induced lupus

• Etiology: 
  • Procainamide
  • Hydralazine
  • Isoniazid
  • Quinidine
  • Methyldopa
  • Diltiazem
  • Sulfasalazine
  • Tumor necrosis factor (TNF) inhibitors (e.g., etanercept, infliximab)
• Pathogenesis theories:
  • Altered drug metabolism
  • Altered response to drug metabolites
  • Abnormal activation of lymphocytes
• Clinical presentation
  • Similar to idiopathic SLE
  • Cutaneous manifestations are generally less common.
  • Severe systemic manifestations are less common, but may vary depending on the offending drug.
  • Duration of medication exposure before onset can vary.
• Diagnosis: associated with positive anti-histone antibodies
• Management: improves with removal of the offending medication

Discoid lupus erythematosus

• Subset of chronic cutaneous lupus
• Clinical presentation:
  • Photodistributed cutaneous lesions
  • May be localized or diffuse
  • Characteristics:
    • Erythematous, violaceous scaly plaques
    • Follicular plugging
  • Results in scarring and atrophy
  • Systemic disease is usually not present.

Neonatal lupus

• Etiology:
  • Passive transfer of autoantibodies from the mother to the fetus
  • Particularly involves anti-Ro and anti-La antibodies
• Clinical presentation:
  • Cutaneous:
    • Often noted at delivery, but may not show until exposure to UV light
    • Reversible
    • Erythematous annular lesions
    • Slight central atrophy
    • Raised margins
    • Scaly
    • Locations: periorbital, scalp, palms, soles, diaper region
  • Cardiac:
    • Occurs between 18 and 25 weeks of gestation
    • Varying levels of atrioventricular heart block and fetal bradycardia
    • Congestive heart failure
    • Myocarditis
    • Aortic dilation
  • Other:
    • Transaminitis
    • Hepatomegaly or hepatitis
    • Cytopenias 
    • Hydrops fetalis
• Diagnosis:
  • Anti-Ro and anti-La antibodies in the mother or child
  • Clinical manifestations (listed above)
• Management:
  • Prenatal:
    • Controversial
    • Fluorinated steroids: dexamethasone, betamethasone
    • Beta-agonists for heart rate < 50/minute
    • Early delivery if in poor overall health
  • Postnatal:
    • Depends on severity of cardiac involvement
    • Observation
    • Cardiac pacemaker for some with complete heart block
    • Rash will typically resolve without scarring.

Diagnosis

Antibody testing

When SLE is initially suspected: ANA

• Nonspecific, but the most sensitive screening test
• Seen in > 95% of cases
• Immunofluorescence pattern may be diffuse or speckled.

If ANA is positive, the following should be evaluated:

• Anti-dsDNA antibodies:
  • Specific for SLE
  • Seen in 70% of cases
  • Correlates with disease activity
• Anti-Sm antibodies:
  • Highly specific, but less sensitive than anti-dsDNA
  • Only seen in 30% of cases
  • Not present in drug-induced lupus
• Anti-histone antibodies: positive in drug-induced lupus
• Antiphospholipid antibodies:
  • Lupus anticoagulant, anti-cardiolipin antibody, and anti-beta2-glycoprotein antibody
  • Associated with thrombotic events and spontaneous abortion
• Anti-Ro or anti-La: 
  • Seen in 20%‒30% of cases
  • Frequently present in those with Sjögren’s syndrome
  • Anti-Ro is associated with neonatal lupus.
• Anti-ribonucleoprotein antibodies:
  • Seen in 25% of cases
  • Associated with mixed connective-tissue disease

Supporting workup

• CBC:
  • Thrombocytopenia 
  • Leukopenia
  • Anemia → should be evaluated for autoimmune hemolysis:
    • ↑ Lactate dehydrogenase
    • ↑ Indirect bilirubin
    • ↓ Haptoglobin
    • Positive direct Coombs test
• ↑ Erythrocyte sedimentation rate (ESR) and CRP
• ↓ Complement component (C3 and C4) levels 
  • Will be normal in drug-induced lupus
  • Correlates with disease activity
• Rule out the following:
  • Hepatitis B and C
  • Borrelia serology (in endemic areas)
  • EBV
• Evaluation for renal involvement:
  • ↑ BUN and creatinine 
  • Urinalysis: 
    • Proteinuria
    • Hematuria
    • RBC casts
  • ↑ Urine protein:creatinine ratio
  • Renal biopsy may be considered to classify the disease and guide management:
    • Class I: minimal mesangial lupus nephritis
    • Class II: mesangial proliferative lupus nephritis
    • Class III: focal proliferative lupus nephritis
    • Class IV: diffuse segmental or diffuse global lupus nephritis
    • Class V: membranous lupus nephritis
    • Class VI: advance sclerosing lupus nephritis

Diagnostic criteria

• Based on the European League Against Rheumatisms/American College of Rheumatology (EULAR/ACR) 2019 classification criteria
• All patients must have an ANA titer > 1:80.
• A score of ≥ 10 with ≥ 1 clinical finding confirms a diagnosis of SLE.
• Previous ACR criteria (from 1997) required 4 of 11 findings.

Mnemonic

To help recall some criteria, remember “SOAP BRAIN MD:”

• Serositis (e.g., pleuritis, pericarditis)
• Oral or nasopharyngeal ulcers (painless)
• Arthritis 
• Photosensitivity
• Blood disorders (e.g., cytopenias)
• Renal disease
• ANAs 
• Immunological disorders (e.g., anti-dsDNA, anti-Sm, antiphospholipid)
• Neurological disorders (e.g., seizures, psychosis)
• Malar rash 
• Discoid rash

Management

As there is no definitive treatment available, management is aimed at controlling acute flares, suppressing symptoms, and preventing organ damage.

General

• Educate the patient about the disease.
• Smoking cessation
• UV protection:
  • Sunscreen
  • Avoid medications that cause photosensitivity.
  • Avoid tanning.
• Isometric exercise
• Relaxation techniques to curb stress
• Acetaminophen and NSAIDs to manage pain

Cutaneous treatment

• Topical corticosteroids
• Topical calcineurin inhibitors
• Hydroxychloroquine

Systemic management

• All patients must be on hydroxychloroquine.
• Mild-to-moderate symptoms:
  • Low dose of glucocorticoids 
  • Steroid-sparing immunosuppressants may be added:
    • Methotrexate
    • Azathioprine
• Severe symptoms with organ damage:
  • High dose of glucocorticoids
  • Immunosuppressive or biological agents:
    • Cyclophosphamide
    • Mycophenolate
    • Rituximab
    • Belimumab (used if disease is resistant to the above therapies)

Prevention of complications

• Prophylaxis for osteoporosis
• Influenza, human papillomavirus, and pneumococcal vaccines
• Suppression of recurrent urinary tract infections
• Blood pressure should be managed to prevent renal damage.

Complications and Prognosis

Lupus nephritis

• Seen in 30% of patients with SLE
• Due to subendothelial deposition of immune complexes
• Patients usually present with nephritic or nephrotic syndromes.
• Management depends on the severity of the disease and may include:
  • Antihypertensive/antiproteinuric therapy:
    • ACE inhibitors
    • Angiotensin II receptor blockers (ARBs)
  • High dose of corticosteroids
  • Immunosuppressants:
    • Azathioprine
    • Mycophenolate
    • Tacrolimus
    • Cyclophosphamide
  • Dialysis

Antiphospholipid syndrome (APS)

• 40% of patients with SLE are positive for APS antibodies.
• Only 20% of patients exhibit symptoms (thrombosis).
• Management: 
  • Anticoagulants
  • Hydroxychloroquine

Libman-Sacks endocarditis

• One of the most common cardiac presentations of SLE
• Non-bacterial endocarditis:
  • Deposition of sterile platelet thrombi on heart valves
  • Commonly affects mitral-aortic valves
• Patients usually present with:
  • Valvular insufficiency
  • Heart failure
  • Embolism
  • Secondary infective endocarditis
• Management:
  • SLE management
  • Systemic anticoagulants
  • Surgery in severe disease

Prognosis

• Rate of survival is very good with optimal therapy.
• 5-year survival: > 90%
• Most common causes of death: 
  • Cardiovascular disease
  • Infections
  • End-stage renal disease
• Poor prognosis has been associated with:
  • ↑ Serum creatinine levels and nephrotic syndrome 
  • Hypertension
  • Anemia, hypoalbuminemia, or hypocomplementemia 
  • Antiphospholipid antibodies
  • Male gender
  • African American ethnicity 
  • Low socioeconomic status

Mnemonic

To recall the 3 most common causes of death in SLE, remember: “Lupus patients die with Redness In their Cheeks.”

• Renal disease
• Infections
• Cardiovascular disease

Differential Diagnosis

• Rheumatoid arthritis: an autoimmune disease resulting in joint inflammation and destruction. Rheumatoid arthritis is typically symmetric with tenderness and swelling of the joints of the hands and feet. Systemic manifestations may include Sjögren’s syndrome, interstitial lung disease, pleural effusion, pericarditis, vasculitis, and anemia. Positive rheumatoid factor and anti-cyclic citrullinated peptide antibodies may be seen. Treatment is with NSAIDs, disease-modifying antirheumatic drugs (DMARDs), steroids, and immunosuppressive medications.
• Adult Still’s disease: a rare, systemic inflammatory disease characterized by daily fevers, arthritis, and an evanescent, salmon-colored rash on the trunk and extremities. Laboratory evaluation will show leukocytosis, transaminitis, negative ANA, and elevated inflammatory markers. Overall, the diagnosis of adult-onset Still’s disease is based on exclusion. Management depends on the severity of the condition. Treatment is with NSAIDs, glucocorticoids, DMARDs, and biological agents.
• Behcet’s disease: inflammatory vasculitis of small and large vessels. Symptoms can include arthritis and painful oral and genital ulcers. Ocular, neurologic, GI, and vascular manifestations are also seen. The diagnosis is based on clinical criteria, and the characteristic SLE antibody test will be negative. Management depends on clinical manifestations. Treatment is with corticosteroids, DMARDs, and TNF inhibitors.
• Fibromyalgia: a nonarticular disorder of unknown etiology that causes generalized pain in the muscles, points of tendon insertion, and soft tissues. Associated symptoms include fatigue, muscle stiffness, cognitive disturbances, depression, and anxiety. Diagnosis is based on clinical criteria. Imaging and laboratory testing will be unremarkable. Management includes exercise and non-opioid analgesics, and is aimed at improving sleep and reducing stress.
• Sjogren’s syndrome: an autoimmune, inflammatory condition of the glandular tissues, resulting in decreased tear and saliva production. Symptoms include dry eyes and mouth. Systemic manifestations include Raynaud’s phenomenon, neuropathy, and cutaneous vasculitis. Diagnosis is based on symptoms, clinical findings, determination of anti-Ro and anti-La antibodies, and salivary-gland biopsy. Management is targeted at achieving symptomatic relief and immunosuppressive therapy is reserved for severe symptoms.
• Sarcoidosis: an inflammatory disorder causing non-caseating granulomas in organs and tissues. The etiology is unclear, and symptoms can vary widely. Patients may develop cough, dyspnea, fatigue, fever, arthritis, erythema nodosum, uveitis, heart block, and neuropsychiatric manifestations. Diagnosis is based on biopsy findings, as the antibody test tends to be negative. Management is with corticosteroids.
• Non-Hodgkin’s lymphoma: a diverse group of malignancies of B cell, T cell, and NK cell origin. Most cases involve the lymph nodes. Non-Hodgkin’s lymphoma often presents with fatigue, fevers, night sweats, weight loss, anemia, and lymphadenopathy. Other symptoms can occur in patients with extranodal involvement (e.g., GI, CNS). Lymph node or bone marrow biopsy is helpful in diagnosis. Management is primarily with chemotherapy, immunotherapy, and targeted therapy.