Systemic Lupus Erythematosus (SLE)

Definition, Prevalence, and Epidemiology

• ~90% of affected individuals are women, most of childbearing age
• US prevalence (CDC National Lupus Registry): ~204,295 cases; overall prevalence 9x higher in women vs. men
• Highest prevalence in Black women, then Hispanic, White, and Asian/Pacific Islander women
• Among men, Black men have the highest prevalence
• Autoantibodies can be detected years before clinical diagnosis

Diagnosis and Classification

• Only a renal biopsy showing Class III or IV lupus nephritis alone reaches 10 points in EULAR/ACR
• ~5% of SLE patients are ANA-negative (excluded from most trials)
• Type 1 lupus: classic inflammatory findings (nephritis, arthritis, vasculitis) - responds to immunosuppression
• Type 2 lupus: fatigue, diffuse pain, depression, cognitive dysfunction, brain fog - less responsive to immunosuppressive therapy

Pathogenesis

Genetics

• Strong genetic component: 24% concordance in monozygotic vs. 2% in dizygotic twins

• 150 susceptibility loci identified by GWAS

• Most common association: MHC region (antigen presentation, complement, cytokines)
• Nearly half of susceptibility loci involve type I interferon (IFN) production or signaling
• Key IFN pathway genes: TLR7, ADAR, IFIH1, SAMHD1, RNASEH2B, TREX1 (nucleic acid sensing/metabolism); DNASE1, DNASE1L3 (nucleic acid degradation); IRF5, IRF7, IRF8, STAT4 (IFN amplification)
• Complement cascade genes (C1Q, C1r, C1s, C2, C4) - deficiency leads to impaired clearance of apoptotic debris and severe SLE

Environmental Triggers

• UV light: alters DNA methylation, generates self-stimulatory nucleic acids, activates keratinocyte immune responses
• Epstein-Barr virus: induces IFN response, activates SLE susceptibility genes
• Gut microbiome: increased gut permeability promotes translocation of microbes into blood, triggering lupus-specific autoantibodies
• Toxins: mercury, pesticides, diet

Innate Immunity

• Defects in innate immune cells lead to increased cellular breakdown and reduced debris clearance
• Plasmacytoid dendritic cells produce large amounts of type I IFN, sensitizing both innate and adaptive immune responses
• Neutrophil NETosis releases autoantigens (nucleic acids, nuclear proteins)

Adaptive Immunity

• Autoreactive T cells activate autoreactive B cells
• B cells produce autoantibodies (anti-dsDNA, anti-Sm) against cellular debris
• Immune complexes deposit in tissues (notably kidneys, skin, joints)
• Monocytes infiltrate tissue, activated by immune complexes via FcgR, inducing local inflammation

Clinical Manifestations

Cutaneous Manifestations

• "Butterfly" malar erythema across nose and cheeks
• Sudden onset, edema, fine scale - correlates with systemic activity
• Histology: hydropic degeneration of basal keratinocytes, dermal edema, perivascular mononuclear infiltrate, dermal mucin
• Direct immunofluorescence: Ig and complement deposits at epidermal basement membrane zone

• Widespread photosensitive, nonscarring eruption
• Two forms: papulosquamous (resembles psoriasis) or annular/polycyclic
• More widespread than discoid LE but less scarring
• Drug-induced SCLE: hydrochlorothiazide, calcium channel blockers, antifungals, proton pump inhibitors
• Most SCLE patients have anti-Ro (SS-A) autoantibodies

• Scarring plaques predominantly on face, scalp, ears
• Can cause permanent hair loss (scarring alopecia)

• Photosensitivity, oral/nasal ulcers, Raynaud's phenomenon, livedo reticularis

Musculoskeletal Manifestations

• Arthritis in the majority of patients; most common initial complaint
• Jaccoud arthropathy: nonerosive, reversible joint deformities (unlike RA), caused by joint capsule inflammation and fibrotic retraction, with MCP subluxation
• Myositis and myalgias may also occur

Renal Manifestations (Lupus Nephritis)

• Class III/IV LN = most severe; Class IV alone meets EULAR/ACR classification threshold
• Monitoring: urine protein-to-creatinine ratio, urinalysis, serum creatinine, complement levels, anti-dsDNA titers

Vascular/Cardiovascular Manifestations

• Accelerated atherosclerosis: major cause of morbidity/premature death; driven by type 1 IFN and vascular injury
• Antiphospholipid syndrome (APS): occurs commonly in SLE; arterial, venous, or small vessel thrombosis in the presence of antiphospholipid antibodies
• Stroke: reported in up to 19% of SLE patients (from atherosclerosis + APS)
• Libman-Sacks endocarditis: fibrinous sterile endocarditis associated with antiphospholipid antibodies; risk for embolic events
• Pericarditis: most common cardiac manifestation; managed with anti-inflammatories, colchicine, anti-IL-1 therapies
• Myocarditis: rarer; can cause left heart failure/arrhythmia

Pulmonary Manifestations

• Pleuritis (most common): with or without exudative effusions
• Acute pneumonitis (imaging may mimic infection)
• Diffuse alveolar hemorrhage with capillaritis
• Interstitial lung disease
• Shrinking lung syndrome: restrictive defect from reduced lung volumes (uncommon)
• Pulmonary arterial hypertension, pulmonary embolism (with or without APS)

Hematologic Manifestations

• Anemia (most common, >50% of cases): mainly anemia of chronic disease
• Also: autoimmune hemolytic anemia (Coombs-positive)
• Leukopenia, lymphopenia
• Thrombocytopenia (immune-mediated)
• All cytopenias may be multifactorial (disease activity, medications, infection)

Neuropsychiatric SLE (NPSLE)

• Seizures, transverse myelitis (linked to APS)
• Cognitive dysfunction, brain fog, depression, anxiety (type 2 lupus features)
• Cerebritis (severe, organ-threatening)
• CNS manifestations are not a recommended indication for belimumab or anifrolumab

Key Autoantibodies in SLE

Pregnancy in SLE

• SLE pregnancies are high risk; disease can flare any trimester
• Higher rates of: pregnancy loss, preterm birth, preeclampsia, IUGR, cesarean section, maternal death
• Highest risk for maternal death: pulmonary arterial hypertension, prior arterial thrombosis, severe end-organ damage - should strongly consider avoiding pregnancy

Neonatal Lupus

• Anti-Ro (SS-A) antibodies cross the placenta and can cause:
  • Transient cutaneous rash or lab abnormalities (resolves)
  • Congenital heart block (can be irreversible if complete)
• Management: fetal echocardiography to screen; fluorinated steroids if 1st- or 2nd-degree heart block detected
• HCQ significantly reduces risk of recurrent congenital heart block

Treatment

General Measures (All Patients)

• Daily sunscreen on sun-exposed areas
• Healthy diet, maintain normal weight
• Avoid smoking (impairs antimalarial efficacy)
• Regular exercise
• Up-to-date vaccinations
• Control of blood pressure, lipids, glucose

Pharmacotherapy

• First-line for ALL patients unless contraindicated
• Prevents flares, increases survival, decreases renal disease, reduces atherosclerosis
• First-line for skin and joint manifestations; most useful drug for fatigue
• Safe in pregnancy and breastfeeding
• Dosing: up to 5 mg/kg/day (actual body weight)
• Monitoring: baseline and annual retinal exams (risk of macular toxicity with long-term use)
• Risk factors for retinal toxicity: higher dose, longer duration

• Short-term use to control acute flares
• Taper to ≤5 mg/day prednisone as quickly as possible
• Discontinue if possible; long-term high-dose use associated with damage accrual

• Methotrexate (MTX)
• Azathioprine (AZA)
• Mycophenolate mofetil (MMF)
• Calcineurin inhibitors (CNI: tacrolimus, cyclosporine)

• Belimumab (anti-BLYS/BLyS): FDA-approved for active SLE; reduces flares, protects against organ damage; not recommended in severe neuropsychiatric disease
• Anifrolumab (anti-IFNAR1, type I IFN receptor blocker): FDA-approved; particularly effective for severe skin disease as add-on; not recommended in severe neuropsychiatric disease

• IV cyclophosphamide (CYC): for cerebritis, myelitis, pneumonitis, mesenteric vasculitis, severe thrombocytopenia
• Rituximab (RTX): anti-CD20; used for refractory disease; can be continued in organ-threatening pregnancy
• High-dose IV glucocorticoids (pulse methylprednisolone)

• Class III/IV: MMF or cyclophosphamide as induction + glucocorticoids; then maintenance MMF or AZA
• Voclosporin (calcineurin inhibitor): FDA-approved for lupus nephritis in combination with MMF
• Belimumab: approved as add-on therapy for active lupus nephritis
• Class V (membranous): MMF is preferred

• Long-term anticoagulation with warfarin or LMWH for thrombotic APS
• Low-dose aspirin + hydroxychloroquine for primary prevention
• Avoid DOACs in APS with triple-positive antibodies

Treat-to-Target Goals

• Remission: Clinical SLEDAI = 0, on HCQ, glucocorticoids ≤5 mg/day
• Lupus Low Disease Activity State (LLDAS): SLEDAI ≤4, HCQ, glucocorticoids ≤5 mg/day, immunosuppressives at stable dose

Drug-Induced Lupus

• Associated with anti-histone antibodies
• Common drugs: hydralazine, procainamide, isoniazid, minocycline, TNF-alpha inhibitors
• Typically resolves on discontinuation of the offending drug
• Renal and CNS involvement rare (unlike SLE)

Monitoring Disease Activity

• SLEDAI (Systemic Lupus Erythematosus Disease Activity Index): widely used clinical score
• BILAG: British Isles Lupus Assessment Group
• Laboratory: CBC, urinalysis, urine protein:creatinine ratio, serum creatinine, complement (C3/C4), anti-dsDNA titers
• CLASI: Cutaneous Lupus Disease Area and Severity Index (for skin disease in trials)