Systemic Lupus Erythematosus¶
Chapter 368 | Part 11: Immune-Mediated, Inflammatory, and Rheumatologic Disorders
KEY CLINICAL POINTS¶
- SLE is a systemic autoimmune disease characterized by autoantibodies, immune complexes, and inflammation causing multiorgan damage.
- The 2019 EULAR/ACR and 2012 SLICC classification criteria are used for clinical trials, with ANA titer ≥ 1:80 required for EULAR/ACR.
- Renal involvement (lupus nephritis) occurs in ~35% of patients, with class III/IV and V being most severe, requiring immunosuppressive therapy.
- Hydroxychloroquine (HCQ) is first-line for skin and arthritis, reducing flares and renal disease risk, with retinal monitoring required.
- Treatment algorithms for non-renal SLE (Fig. 368-4) and lupus nephritis (Fig. 368-5) emphasize corticosteroid tapering, immunosuppressants, and biologics like belimumab.
1. DEFINITION & OVERVIEW¶
Systemic lupus erythematosus (SLE) is a chronic, multisystem autoimmune disease characterized by autoantibodies, immune complexes, and inflammation causing tissue damage. It affects ~90% women, predominantly of childbearing age, but can occur in all demographics. Key features include cutaneous, musculoskeletal, renal, and neurological manifestations. Autoantibodies (e.g., anti-dsDNA, anti-Sm) and immune complexes drive pathogenesis.
Table 368-1: Clinical Manifestations of SLE¶
| Category | Manifestations |
|---|---|
| Constitutional | Fatigue, malaise, fever, weight loss, anorexia |
| Cutaneous | Generalized photosensitivity, oral/nasal ulcers, alopecia |
| Musculoskeletal | Arthralgia, myalgia, polyarthritis, Jaccoud hand |
| Hematologic | Anemia, leukopenia, thrombocytopenia |
| Cardiopulmonary | Pleuritis, pericarditis, myocarditis, pulmonary hypertension |
| Renal | Proteinuria ‡500 mg/24h, cellular casts, nephrotic syndrome |
Table 368-2: Autoantibodies in SLE¶
| Antibody | Prevalence (%) | Clinical Associations |
|---|---|---|
| ANA | 95 | Sensitivity for SLE, not specific |
| Antibody | Prevalence (%) | Clinical Associations |
|---|---|---|
| Anti-dsDNA | 70 | Specific for SLE, correlates with nephritis |
| Anti-Sm | 30 | Most specific for SLE, associated with CNS manifestations |
| Anti-Ro (SS-A) | 30 | Associated with neonatal lupus, sicca syndrome |
| Anti-La (SS-B) | 20 | Associated with anti-Ro |
| Antihistone | 70 | Drug-induced lupus |
1.1 Iatrogenic Autoimmunity¶
Immune checkpoint inhibitors (ICIs) and drugs like antimalarials, TNF inhibitors, and antiseizure medications can induce autoimmunity. Drug-induced lupus (DIL) is characterized by antihistone antibodies and reversible symptoms upon drug discontinuation.
1.2 Prevention & Treatment of Autoimmunity¶
Early intervention strategies for T1DM, RA, and SLE are under investigation. Personalized medicine targeting dysregulated immune cells while sparing critical functions is a future goal.
2. EPIDEMIOLOGY¶
SLE affects ~5 million people globally, with a female-to-male ratio of 9:1. Prevalence is highest in Black women (204,295 cases in the U.S.), followed by Hispanic, White, and Asian/Pacific Islander women. Risk factors include genetic predisposition, environmental triggers (UV light, infections), and comorbidities like APS. Ethnic disparities in disease severity and outcomes are well-documented.
2.1 Demographics¶
Predominantly affects women of childbearing age (15–44 years), but can occur in neonates, children, and men. Black women have the highest prevalence, while White men have the lowest.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
SLE results from genetic susceptibility (150+ loci, including IFN pathways), environmental triggers (UV light, infections, toxins), and immune dysregulation. Key mechanisms include defective clearance of apoptotic debris, type 1 IFN overproduction, and aberrant innate/adaptive immune responses. The complement system and Fc γ receptors play critical roles in immune complex-mediated tissue damage.
3.1 Genetic Factors¶
Genome-wide association studies (GWAS) identify >150 susceptibility loci, with HLA-DR and IFN pathways being central. Genes like IRF5, STAT4, and TREX1 are associated with increased risk.
3.2 Environmental Triggers¶
UV light, Epstein-Barr virus, smoking, and toxins (mercury, pesticides) contribute to disease onset. Gut microbiome dysbiosis may increase gut permeability, promoting autoantibody production.
4. CLINICAL FEATURES¶
SLE presents with diverse manifestations: cutaneous (malar rash, discoid lupus), musculoskeletal (arthritis, myositis), renal (nephritis), neurological (cognitive dysfunction, seizures), hematologic (cytopenias), and cardiovascular (pericarditis, pulmonary hypertension). Systemic symptoms include fatigue, fever, and weight loss.
4.1 Cutaneous Manifestations¶
Acute (malar rash), subacute (SCLE), and chronic (discoid lupus) rashes. Photosensitivity and scarring are common. Raynaud’s phenomenon occurs in ~1/3 of patients. Lupus nephritis affects ~35% of patients, with class III/IV (focal/diffuse proliferative) and class V (membranous) being most severe. Proteinuria ≥ 500 mg/24h and cellular casts are diagnostic.
5. DIFFERENTIAL DIAGNOSIS¶
Differential diagnoses include other autoimmune diseases (RA, Sjögren’s), infections (HIV, hepatitis), and malignancies (lymphoma). Drug-induced lupus (DIL) must be distinguished from SLE, with antihistone antibodies and reversible symptoms upon drug discontinuation.
6. INVESTIGATIONS & DIAGNOSIS¶
Diagnosis relies on clinical and laboratory criteria (EULAR/ACR, SLICC). Key tests include ANA (titer ≥ 1:80), anti-dsDNA, anti-Sm, complement levels (C3/C4), and renal function (eGFR, UPCr). Renal biopsy classifies lupus nephritis (Fig. 368-3).
6.1 Laboratory Tests¶
ANA, anti-dsDNA, anti-Sm, complement levels, and urine analysis (UPCr, proteinuria). Autoantibodies like anti-Ro/SS-A are associated with neonatal lupus and photosensitivity.
7. MANAGEMENT & TREATMENT¶
Treatment is tailored to disease activity and organ involvement. HCQ is first-line for skin and arthritis, with corticosteroids for flares. Immunosuppressants (MMF, cyclophosphamide) and biologics (belimumab, voclosporin) are used for severe cases. Renal disease requires ACE/ARBs and SGLT2 inhibitors.
Table 368-1: Treatment of Non-Renal SLE¶
| Disease Severity | First-Line Therapy | Second-Line Therapy |
|---|---|---|
| Mild | HCQ | MTX/AZA |
| Moderate | HCQ + low-dose GC | MMF |
| Severe | MMF + rituximab/belimumab | Cyclophosphamide |
Table 368-2: Treatment of Lupus Nephritis¶
| Nephritis Class | Therapy | Notes |
|---|---|---|
| Class III/IV | MMF + low-dose CYC | Avoid in pregnancy |
| Class V | MMF + ACE/ARBs | SGLT2 inhibitors for eGFR <60 |
| Active Nephritis | Belimumab/voclosporin | Triple therapy with MMF/GC |
7.1 Non-Renal SLE¶
Mild: HCQ + sun protection. Moderate: MTX/AZA + low-dose GC. Severe: MMF + rituximab or belimumab. Avoid MMF in pregnancy; use azathioprine instead.
7.2 Lupus Nephritis¶
Class III/IV: MMF + low-dose CYC. Class V: MMF + ACE/ARBs. Belimumab/voclosporin are first-line for active nephritis. Monitor eGFR and adjust therapy based on renal response.
8. PROGNOSIS & COMPLICATIONS¶
Prognosis varies by disease activity and organ involvement. Renal failure, cardiovascular disease, and infections are leading causes of mortality. Long-term corticosteroid use increases risk of osteoporosis, diabetes, and malignancies (e.g., lymphoma, skin cancers).
8.1 Pregnancy Outcomes¶
SLE pregnancies are high-risk, with increased risks of miscarriage, preterm birth, and preeclampsia. HCQ reduces flares, while belimumab/anifrolumab should be avoided preconception.
9. SPECIAL CONSIDERATIONS¶
Pregnancy: HCQ is safe; avoid MMF/cyclophosphamide. Pediatrics: Monitor for nephritis and CNS involvement. Elderly: Adjust corticosteroid doses and manage comorbidities. DIL requires drug discontinuation and antihistone antibody testing.
10. KEY POINTS & CLINICAL PEARLS¶
- Use EULAR/ACR criteria for SLE diagnosis, with ANA titer ≥ 1:80. 2. Monitor UPCr and eGFR for renal disease. 3. HCQ is first-line for skin and arthritis, with retinal monitoring. 4. Belimumab/voclosporin are first-line for active nephritis. 5. Avoid MMF in pregnancy; use azathioprine instead. 6. DIL is reversible with drug discontinuation and antihistone antibodies.