What is the initial management and treatment for lupus?

Initial Management and Treatment for Lupus

All patients with systemic lupus erythematosus should be started on hydroxychloroquine immediately, as it is the cornerstone of therapy and has been associated with significant reduction in mortality, disease activity, and organ damage. 1, 2

First-Line Universal Therapy

• Hydroxychloroquine is mandatory for all SLE patients unless contraindicated, with a recommended dosage of 200-400 mg daily (not exceeding 5 mg/kg actual body weight to minimize retinopathy risk). 3, 1, 2
• This medication reduces disease flares, limits renal and cardiovascular damage, and improves overall survival. 4
• Hydroxychloroquine should be taken with food or milk, and tablets should not be crushed or divided. 1

Disease Severity-Based Treatment Algorithm

Mild to Moderate Non-Organ Threatening Disease

For patients with arthritis, rash, fatigue, or serositis without major organ involvement:

• Continue hydroxychloroquine as the foundation. 3, 1
• Add low-dose glucocorticoids (prednisone ≤10 mg/day) for symptom control during flares. 3
• Consider NSAIDs for musculoskeletal symptoms and serositis, though use cautiously due to increased risk of renal side effects, aseptic meningitis, and hepatotoxicity in SLE patients. 5
• Add azathioprine (1-2 mg/kg/day) or methotrexate as steroid-sparing agents if glucocorticoid tapering is unsuccessful. 3

Critical caveat: NSAIDs carry heightened risks in SLE, particularly acute renal failure in patients with lupus nephritis, and increased rates of cutaneous reactions and hepatotoxicity. 5

Moderate to Severe Organ-Threatening Disease

For patients with lupus nephritis (Class III or IV), severe hematologic manifestations, or neuropsychiatric lupus:

Lupus Nephritis - Initial Induction Therapy

The 2024 KDIGO guidelines provide four equally recommended first-line options: 6

1. Mycophenolate mofetil (MMF) 1.0-1.5 g twice daily or mycophenolic acid 0.72-1.08 g twice daily, PLUS glucocorticoids 6
2. Low-dose IV cyclophosphamide (500 mg every 2 weeks for 6 doses), PLUS glucocorticoids 6
3. Belimumab (10 mg/kg IV every 2 weeks for 3 doses, then every 4 weeks) combined with either MMF or cyclophosphamide, PLUS glucocorticoids 6, 7
4. MMF plus calcineurin inhibitor (voclosporin 23.7 mg twice daily) when eGFR >45 mL/min/1.73 m², PLUS glucocorticoids 6

Glucocorticoid regimen for lupus nephritis: 6, 4

• IV methylprednisolone pulses (500-750 mg for 1-3 days initially)
• Followed by oral prednisone 0.5-0.6 mg/kg/day (maximum 40 mg) for weeks 0-2
• Taper to 0.3-0.4 mg/kg/day for weeks 3-4
• Progressive reduction targeting ≤5 mg/day by week 25 or beyond

Selection guidance: Low-dose cyclophosphamide is preferred for patients with adherence concerns to oral regimens. 3, 6 MMF is generally first-line for most patients due to lower gonadotoxicity compared to cyclophosphamide. 3

Lupus Nephritis - Maintenance Therapy

After achieving response (typically 6-12 months):

• Mycophenolate mofetil 750-1000 mg twice daily or mycophenolic acid 540-720 mg twice daily is the preferred maintenance agent. 6
• Azathioprine 1-2 mg/kg/day is an alternative for patients intolerant to MMF. 6
• Continue hydroxychloroquine indefinitely. 4
• Maintain lowest possible glucocorticoid dose (goal <5 mg/day). 6

Severe Hematologic Disease

For thrombocytopenia (platelets <30,000/mm³) or autoimmune hemolytic anemia:

• High-dose glucocorticoids (IV methylprednisolone pulses 1-3 days) combined with an immunosuppressive agent. 3
• Azathioprine, MMF, or cyclosporine as steroid-sparing agents (cyclosporine has least myelotoxicity). 3
• IV immunoglobulin (IVIG) in acute phase for inadequate response to glucocorticoids or to avoid infectious complications. 3
• Rituximab should be considered for refractory cases or relapses during glucocorticoid tapering. 3

Neuropsychiatric Lupus (NPSLE)

Treatment depends on the underlying mechanism:

• For inflammatory NPSLE: Glucocorticoids and/or immunosuppressive agents (MMF, azathioprine, cyclophosphamide). 3
• For thrombotic/embolic NPSLE: Anticoagulation when antiphospholipid antibodies are present. 3
• For mixed or unclear cases: Consider combination of immunosuppression and anticoagulation. 3

Critical step: Comprehensive workup is mandatory to exclude mimics (infections, malignancy) before attributing neuropsychiatric symptoms to SLE. 3

Essential Adjunctive Therapies for All Patients

• ACE inhibitors or ARBs for patients with proteinuria or hypertension. 6, 4
• SGLT2 inhibitors for renal protection in lupus nephritis. 6
• Calcium and vitamin D supplementation with bone density monitoring for patients on glucocorticoids. 6
• Infection prophylaxis: Screen for HBV, HCV, HIV; vaccinate for hepatitis B. 6
• Fertility preservation: Offer gonadotropin-releasing hormone agonists or gamete cryopreservation before cyclophosphamide therapy. 6

Monitoring Strategy

Initial intensive monitoring (first 2-4 months):

• Every 2-4 weeks: serum creatinine, eGFR, urinalysis, urine protein-to-creatinine ratio, complete blood count. 4
• Complement levels (C3, C4) and anti-dsDNA antibodies. 4
• Blood pressure and weight at each visit. 4

After stabilization: Adjust frequency based on treatment response, but maintain at least every 3 months for high-risk patients. 3

Management of Inadequate Response

If no improvement or worsening after 3-6 months: 3

1. Verify medication adherence (nonadherence may exceed 60% in SLE). 3
2. Check drug levels (mycophenolic acid levels if on MMF). 3
3. Repeat kidney biopsy if concern for chronicity or alternative diagnosis. 3
4. Switch to alternative recommended regimen or add rituximab for refractory disease. 3

Common pitfall: Switching from oral to IV cyclophosphamide should be considered when nonadherence is suspected, as this ensures drug delivery. 3

Treatment Goals and Response Definitions

Target complete remission for best long-term outcomes: 3, 6

• Proteinuria <0.5 g/g (or <0.7 g/g for primary endpoint)
• Stable or improved kidney function (eGFR within 10-15% of baseline)
• Minimal extrarenal disease activity
• Glucocorticoid dose ≤5 mg/day

Timeline: Response assessment should occur at 6-12 months, though complete response may take longer than 12 months. 3