Systemic Lupus Erythematosus (SLE)

What Is It?

Epidemiology

• Affects approximately 1 in 1,000-2,500 people in the general population
• Far more common in African American women (up to 1 in 250, ages 18-65)
• Predominantly affects women of reproductive age (15-40 years)
• Female:male ratio is 2:1 before puberty and 4:1 after puberty
• Strong familial tendency; associated with MHC genes DR2, DR3, DR4, and DR5
• Environmental triggers include infections, UV sunlight, stress, drugs, and toxins

Pathophysiology

• B cell overactivity producing antinuclear antibodies (ANAs)
• The most disease-specific antibodies are anti-dsDNA and anti-Sm (Smith antigen) - found almost exclusively in SLE
• Immune complex deposition activates complement and causes end-organ inflammation
• T cell, B cell, and monocyte dysfunction all contribute

Clinical Features

Mucocutaneous (>90% of patients)

• Malar (butterfly) rash - fixed erythema over cheeks sparing the nasolabial folds; present in ~1/3 of patients; often triggered by sun exposure
• Subacute cutaneous LE (SCLE) - annular or papulosquamous lesions on sun-exposed areas; associated with anti-Ro/SS-A antibodies in ~70%; does NOT scar
• Discoid LE (DLE) - raised erythematous plaques with thick scales; typically on face, neck, scalp, ears; DOES cause scarring with hypopigmented atrophic centers
• Photosensitivity (1/3 to 2/3 of patients)
• Oral/nasal/vaginal ulcers, alopecia, palpable purpura

Joints

• Nonerosive arthritis of 2+ peripheral joints (tenderness, swelling, effusion)

Kidneys (Lupus Nephritis)

• Persistent proteinuria >0.5 g/day, or cellular casts
• One of the most serious complications

Cardiovascular / Serositis

• Pleuritis, pericarditis
• Antiphospholipid antibody syndrome: venous/arterial thrombosis, livedo reticularis

Neurologic

• Seizures or psychosis (in the absence of metabolic causes)

Hematologic

• Hemolytic anemia, leukopenia (<4000/mm³), lymphopenia (<1500/mm³), thrombocytopenia (<100,000/mm³)

Diagnostic Criteria (ACR - 11 Criteria)

Laboratory Findings

• ANA - positive in >95% of SLE; highly sensitive but not specific
• Anti-dsDNA and anti-Sm - highly specific for SLE
• Anti-Ro/SS-A and anti-La/SS-B - associated with SCLE and neonatal lupus
• Complement (C3, C4) - low during active disease
• Anemia, leukopenia, thrombocytopenia on CBC
• Elevated creatinine, proteinuria, hematuria in renal involvement
• False-positive VDRL/RPR (syphilis test)

Approach to Cutaneous Lupus

Management

General Principles

• Avoid precipitating factors, especially sun exposure (use sunscreen, protective clothing)
• Monitor for organ involvement at each visit
• Long-term physician-patient relationship between family doctor and rheumatologist is important

Pharmacologic Treatment by Severity

• NSAIDs - first-line for myositis, serositis, arthritis
• Topical corticosteroids - for cutaneous lupus (SOR: B)
• Hydroxychloroquine (antimalarial) - for persistent cutaneous lesions; also reduces flares and has cardioprotective effects

• Prednisone 0.5 mg/kg/day for arthritis/serositis/constitutional symptoms
• Prednisone 1 mg/kg/day for nephritis and CNS disease
• IV methylprednisolone for severe hemolytic anemia

• Immunosuppressives: cyclophosphamide, azathioprine, mycophenolate mofetil (especially for lupus nephritis)
• If no steroid response after 7 weeks, add immunosuppressive therapy

• Warfarin (INR 2-3) for venous/arterial thrombosis; often lifelong

• Dialysis or kidney transplantation

Outcome

• 5-year survival: 90% with modern treatment

• 90% of treated patients survive at least 15 years

• SLE was once considered a universally progressive, terminal disease; outcomes have dramatically improved

Lupus Variants

Sjögren Syndrome

Definition

Primary vs. Secondary

Epidemiology

• Estimated prevalence: 1-3% of the population
• Most common in the 4th to 5th decades of life
• >90% of patients are women
• Associated with HLA B8 and DR3

Pathophysiology

1. Aberrant autoimmune activation
2. Dense lymphocytic infiltration of exocrine glands
3. B-cell overstimulation - excess immunoglobulins and autoantibodies; autoreactive B-cell clones escape tolerance checkpoints
4. Formation of germinal centers within salivary glands
5. Increased follicular helper T cells driving B-cell responses
6. Production of characteristic autoantibodies: anti-Ro/SS-A and anti-La/SS-B

Clinical Features

Sicca (Glandular) Manifestations

• Difficulty chewing, swallowing, and speaking
• Intolerance to acidic/spicy foods
• Dental caries (accelerated, due to reduced saliva)
• Adherence of food to buccal mucosa
• Smooth, fissured tongue with papillary atrophy
• Absence of pooled saliva in floor of mouth
• Scant or cloudy saliva from ducts
• Candida albicans overgrowth (common)
• Parotid gland enlargement in 25-66% of patients - may be unilateral initially, usually becomes bilateral; episodic or chronic

• Foreign body sensation - "gritty" or "sandy" feeling
• Dilated bulbar conjunctival vessels, periorneal injection
• Corneal/conjunctival epithelial destruction
• Lacrimal gland enlargement (occasionally)

Systemic (Extraglandular) Manifestations

Diagnosis

Objective Tests

Serology

• Anti-Ro/SS-A - most sensitive (70-90% in SCLE overlap; present in SS)
• Anti-La/SS-B - more specific, less sensitive
• ANA - positive in 60-80%
• Elevated RF (>1:320) in many patients
• Hypergammaglobulinemia, cryoglobulins
• Complement (C3/C4) - generally normal in SS (unlike SLE, where it is low)
• B-cell subset analysis recommended

San Diego Criteria for Definite SS

1. Objective signs of ocular dryness (Schirmer <8 mm AND positive Rose Bengal)
2. Objective signs of dry mouth (reduced parotid flow AND positive minor salivary gland biopsy - focus score ≥1)
3. Serologic evidence of systemic autoimmunity (elevated RF >1:320, ANA >1:320, or anti-SS-A/SS-B)

Exclusions

Differential Diagnosis

• Medications (most common cause of xerostomia) - sedatives, antipsychotics, antidepressants, antihistamines, diuretics
• Sarcoidosis, lymphoma
• HIV, hepatitis C infection
• Radiation sialadenitis (>4,000 cGy causes permanent secretory hypofunction)
• Diabetes mellitus, cystic fibrosis
• Bell palsy, MS (neuropathic glandular dysfunction)

Management

Ocular (Dry Eye)

• Artificial tears (monitor for blepharitis from preservatives)
• Punctal plugs - collagen (temporary, dissolve in 2 days) or silicone (durable, removable); can progress to permanent punctal occlusion surgery
• Cyclosporine ophthalmic drops - FDA approved for keratoconjunctivitis sicca; objective and subjective improvement
• Humidifiers
• Patching for corneal ulceration

Oral (Dry Mouth)

• Frequent sips of water; sugarless gum or mints (stimulate residual function)
• Artificial saliva (Salivart, Mouth Kote)
• Pilocarpine (muscarinic agonist) 5 mg three to four times daily - most used systemic sialagogue; side effects: flushing, sweating, urinary frequency
• Cevimeline (also a muscarinic agonist) - alternative secretagogue
• Meticulous fluoride dental care to prevent caries
• Topical antifungal troches for Candida overgrowth

Systemic Disease

• NSAIDs and hydroxychloroquine (antimalarials) - for arthralgias and systemic symptoms
• Corticosteroids - for tubulointerstitial nephritis (usually responds well), and severe extraglandular complications
• Immunosuppressives (cyclophosphamide, azathioprine) - for refractory severe disease, necrotizing vasculitis
• Rituximab (anti-CD20) - B-cell depletion therapy; improves xerostomia, fatigue, and joint tenderness; not beneficial for low disease activity alone; used with corticosteroids for systemic involvement
• Belimumab and abatacept - small preliminary trials show promising results
• Sialendoscopy - for recurrent sialadenitis; duct dilation and washout; may allow lower-intensity medical therapy

Lymphoma Surveillance