What is the recommended treatment for a 28‑year‑old African‑American woman with biopsy‑proven lupus nephritis who stopped immunosuppressive therapy a month ago and now presents with generalized arthralgias, heavy proteinuria and bilateral hydronephrosis indicating a nephritic flare?

Treatment of Lupus Nephritis Flare After Premature Immunosuppression Discontinuation

Restart immunosuppressive therapy immediately with mycophenolate mofetil (MMF) 2-3 g/day combined with glucocorticoids, as this patient has experienced a lupus nephritis flare after prematurely stopping treatment only one month ago. 1

Immediate Assessment Required

Before initiating treatment, rapidly evaluate the following parameters:

• Quantify proteinuria with 24-hour urine collection or spot urine protein-to-creatinine ratio to establish baseline severity 1
• Measure serum creatinine and estimated GFR to assess for any deterioration in renal function compared to one year ago 1
• Check complement levels (C3, C4) and anti-dsDNA antibodies as serological markers of disease activity 1
• Evaluate for bilateral hydronephrosis etiology with renal ultrasound to rule out obstructive causes requiring urgent intervention 1
• Assess medication adherence history since non-adherence occurs in >60% of lupus patients and may explain apparent treatment failure 2

Recommended Induction Treatment Regimen

First-Line Therapy

Mycophenolate mofetil (MMF) 2-3 g/day (or mycophenolic acid 1.44-2.16 g/day) is the preferred agent for this lupus nephritis flare, as it has superior efficacy compared to azathioprine and comparable efficacy to cyclophosphamide with better tolerability. 1

Glucocorticoid regimen:

• Start with intravenous methylprednisolone 500-750 mg daily for 3 consecutive days to achieve rapid disease control 1
• Follow with oral prednisone 0.3-0.5 mg/kg/day (approximately 20-35 mg/day for a typical adult) 1
• Taper to ≤7.5 mg/day by 3-6 months to minimize glucocorticoid toxicity 1

Alternative or Add-On Therapy

For patients with heavy proteinuria (nephrotic-range), consider adding tacrolimus 0.05-0.1 mg/kg/day to MMF as "triple therapy," which shows higher complete remission rates (33.1% vs 7.8%) in membranous lupus nephritis. 1, 3

Belimumab 10 mg/kg IV (days 0,14,28, then every 28 days) can be added to standard therapy if inadequate response at 3-4 months, as it demonstrated significant improvement in renal response rates (43% vs 32% for placebo) in the pivotal lupus nephritis trial. 1, 3, 4

Essential Supportive Measures

• Continue hydroxychloroquine indefinitely at ≤5 mg/kg actual body weight, as it reduces risk of kidney flares, end-stage kidney disease, and death 1, 3
• Initiate ACE inhibitor or ARB at maximum tolerated dose to reduce proteinuria, regardless of baseline blood pressure 3, 5
• Target blood pressure <125/75 mmHg given the presence of heavy proteinuria 3, 5
• Restrict sodium intake to <2 g/day to potentiate antiproteinuric effects 3

Role of Repeat Kidney Biopsy

Consider repeat kidney biopsy if:

• Uncertainty exists about whether symptoms represent active inflammation versus chronic damage 1, 3
• The histological class may have evolved after one year, which would guide therapeutic choice 3
• Persistent proteinuria despite treatment, to distinguish active disease from irreversible scarring 1

However, given the clear clinical picture of flare after recent treatment discontinuation, empiric treatment should not be delayed while awaiting biopsy. 5

Treatment Response Monitoring

At 3 months: Expect ≥25% reduction in proteinuria and stabilization of kidney function (±10-15% of baseline eGFR). 1, 3

At 6 months: Aim for partial response defined as ≥50% reduction in proteinuria to subnephrotic levels (<3 g/24h) with stable renal function. 1

At 12 months: Target complete renal response with proteinuria <0.5-0.7 g/24h and normal or near-normal renal function (within 10% of baseline if previously abnormal). 1

Duration of Maintenance Therapy

Critical pitfall to avoid: This patient stopped treatment after only one year, which is far too early. 1, 2

• Minimum duration of maintenance immunosuppression is 3-5 years after achieving remission, as most renal flares occur within the first 5-6 years following treatment initiation 1, 2, 3
• MMF induction should be followed by MMF maintenance (not azathioprine), as switching from MMF to azathioprine increases relapse risk 1
• Gradual tapering is essential prior to complete withdrawal; abrupt discontinuation significantly increases flare risk 1, 2

Management of Generalized Joint Pain

The arthralgias are likely manifestations of the lupus flare itself rather than a separate issue. 2, 3

• Controlling disease activity with appropriate immunosuppression will likely improve joint symptoms within 3-4 weeks 2
• Short-term glucocorticoid bridge (as outlined above) provides rapid symptom relief while waiting for immunosuppressive agents to take effect 1, 2
• Assess for other contributors such as anemia, hypothyroidism, or vitamin D deficiency that may exacerbate fatigue 2

Special Considerations for African-American Patients

• African-American ethnicity is an independent risk factor for renal flare after achieving remission 6
• Some evidence suggests MMF may be more efficacious than cyclophosphamide in African-American patients with lupus nephritis 1
• This population may require more aggressive maintenance therapy and longer treatment duration before considering discontinuation 6

If Inadequate Response Occurs

At 3-4 months, if response is inadequate:

• Switch to alternative first-line agent (cyclophosphamide if not previously used excessively) 1
• Add belimumab 10 mg/kg IV to existing MMF regimen 1, 3, 4
• Consider rituximab (B-cell depleting therapy), which shows 50-80% response rates in refractory lupus nephritis 1

Verify adherence with drug level monitoring where available before declaring treatment failure. 1, 2