# Systemic Lupus Erythematosus: Diagnosis and Flare Management

## Introduction

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by multisystem inflammation and a relapsing-remitting course. It predominantly affects women of childbearing age, with higher prevalence and severity in Black, Hispanic, and Asian populations. The internist must recognize lupus flares, differentiate them from infections, and manage both acute exacerbations and chronic disease.

## Epidemiology and Pathophysiology

- Female-to-male ratio approximately **9:1**; peak onset ages 15-45
- Genetic susceptibility, hormonal factors, and environmental triggers (UV light, infections, medications)
- Loss of immune tolerance leads to **anti-nuclear antibody (ANA) production** and immune complex deposition
- End-organ damage results from immune complex-mediated inflammation and complement activation

## Clinical Manifestations

### Constitutional

- Fatigue, fever, weight loss; fever in lupus must always prompt evaluation for infection

### Mucocutaneous

- **Malar (butterfly) rash**: erythema over cheeks and nose, sparing nasolabial folds
- **Discoid lupus**: scarring, plaque-like lesions; can cause permanent alopecia
- Photosensitivity, oral ulcers (usually painless), non-scarring alopecia

### Musculoskeletal

- **Non-erosive inflammatory arthritis**: symmetric, small joint involvement; can mimic rheumatoid arthritis
- Jaccoud arthropathy: reducible joint deformities without erosions
- Avascular necrosis, especially with chronic corticosteroid use

### Renal

- **Lupus nephritis** occurs in up to 50% of patients; major determinant of prognosis
- Screen with urinalysis and spot urine protein-to-creatinine ratio at every visit
- Renal biopsy for classification (ISN/RPS Class I-VI); guides treatment intensity
- Class III (focal) and Class IV (diffuse) proliferative nephritis require aggressive immunosuppression

### Hematologic

- **Cytopenias**: autoimmune hemolytic anemia (positive Coombs), leukopenia, lymphopenia, thrombocytopenia
- Lymphopenia is common and correlates with disease activity

### Cardiopulmonary

- Pericarditis (most common cardiac manifestation), myocarditis, Libman-Sacks endocarditis
- Pleuritis, interstitial lung disease, shrinking lung syndrome, pulmonary hypertension
- Accelerated atherosclerosis; cardiovascular disease is a leading cause of late mortality

### Neuropsychiatric

- Cognitive dysfunction, headache, seizures, psychosis, cerebrovascular disease
- **Antiphospholipid syndrome** overlap: thrombosis, pregnancy morbidity

![Clinical manifestations of SLE organized by organ system](/images/residency/sle-clinical-manifestations.jpg)

## Diagnosis

### 2019 EULAR/ACR Classification Criteria

- **Entry criterion**: ANA >= 1:80 (highly sensitive)
- Additive scoring system across domains: clinical (constitutional, hematologic, neuropsychiatric, mucocutaneous, serosal, musculoskeletal, renal) and immunologic (anti-dsDNA, anti-Smith, antiphospholipid, complement)
- Score >= 10 classifies as SLE
- **Do not attribute to SLE if better explained by another condition**

### Key Serologies

| Antibody / Marker | Sensitivity | Specificity | Clinical Association |
|------------------|-------------|-------------|---------------------|
| ANA | ~98% | Low | Screening test; negative excludes SLE |
| Anti-dsDNA | ~70% | High | Nephritis; correlates with activity |
| Anti-Smith | ~30% | ~99% | Most specific for SLE |
| Anti-Ro/SSA | ~30-40% | Moderate | Neonatal lupus, photosensitivity, sicca |
| Anti-La/SSB | ~15-20% | Moderate | Neonatal lupus, sicca |
| C3/C4 (complement) | N/A | N/A | Low = active disease/consumption |

- **ANA**: sensitive (~98%) but not specific; a negative ANA essentially excludes SLE
- **Anti-dsDNA**: highly specific; levels correlate with disease activity, especially nephritis
- **Anti-Smith**: most specific antibody for SLE (~99%)
- **Complement levels (C3, C4)**: low levels indicate active disease and consumption
- **Anti-Ro/SSA and Anti-La/SSB**: associated with neonatal lupus, photosensitivity, sicca symptoms

## Flare Assessment

### Distinguishing Flare from Infection

- Both can present with fever, elevated inflammatory markers, cytopenias
- **Flare clues**: rising anti-dsDNA, falling complement (C3/C4), active urine sediment, new rash
- **Infection clues**: procalcitonin elevation, localizing symptoms, positive cultures
- Immunosuppressed patients are at high risk for infection; maintain a low threshold for workup

### Monitoring Disease Activity

- Serial anti-dsDNA titers and complement levels
- Urinalysis with microscopy at each visit
- CBC for cytopenias
- Validated indices: SLEDAI, BILAG

![Flowchart for distinguishing lupus flare from infection in the febrile SLE patient](/images/residency/sle-flare-vs-infection.jpg)

## Management

### Foundational Therapy

- **Hydroxychloroquine**: cornerstone of SLE treatment for ALL patients unless contraindicated
- Reduces flares, damage accrual, thrombosis risk, and mortality
- Requires annual ophthalmologic screening for retinal toxicity after 5 years (or sooner with risk factors)
- Do **not** discontinue during pregnancy; safe and protective

### Mild-to-Moderate Disease

- Low-dose corticosteroids for flares; taper as quickly as possible
- **Methotrexate** or **azathioprine** as steroid-sparing agents for arthritis, serositis, skin disease
- Belimumab (anti-BLyS): FDA-approved add-on therapy; reduces flare frequency

### Severe Disease (Nephritis, Cerebritis, Severe Cytopenias)

- **Induction**: mycophenolate mofetil or IV cyclophosphamide + corticosteroids
- **Maintenance**: mycophenolate mofetil or azathioprine
- **Voclosporin**: calcineurin inhibitor approved as add-on for lupus nephritis
- Rituximab: used off-label for refractory disease
- Goal: minimize corticosteroid exposure; target prednisone <= 7.5 mg/day or off

### Preventive Care

- Aggressive cardiovascular risk factor management
- Bone density monitoring with chronic corticosteroid use
- Immunizations (avoid live vaccines on immunosuppression)
- Sun protection and UV avoidance
- Contraception counseling; plan pregnancies during disease quiescence

![Treatment algorithm for SLE stratified by disease severity](/images/residency/sle-treatment-algorithm.jpg)

## Key Clinical Pearls

- Hydroxychloroquine is the single most important medication in SLE; it reduces mortality
- A rising anti-dsDNA with falling complement suggests impending or active flare
- Always check a urinalysis in SLE patients presenting with new symptoms; silent nephritis is common
- Infection is a leading cause of death in SLE; do not assume fever is always a flare
- Minimize corticosteroid exposure; use steroid-sparing agents early

## References

1. Aringer M, Costenbader K, Daikh D, et al. 2019 European League Against Rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus. *Arthritis Rheumatol*. 2019;71(9):1400-1412.
2. Fanouriakis A, Kostopoulou M, Alunno A, et al. 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus. *Ann Rheum Dis*. 2019;78(6):736-745.
3. Hahn BH, McMahon MA, Wilkinson A, et al. American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis. *Arthritis Care Res*. 2012;64(6):797-808.
4. Ruiz-Irastorza G, Ramos-Casals M, Brito-Zeron P, Khamashta MA. Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus. *Ann Rheum Dis*. 2010;69(1):20-28.