What IV cyclophosphamide induction regimen (dose, schedule, and precautions) is recommended for severe systemic lupus erythematosus, such as proliferative lupus nephritis or central nervous system involvement?

IV Cyclophosphamide Regimen for Severe Systemic Lupus Erythematosus

For severe SLE manifestations including proliferative lupus nephritis (Class III/IV) and neuropsychiatric lupus, use the low-dose Euro-Lupus regimen: IV cyclophosphamide 500 mg every 2 weeks for 6 doses (total 3 grams), combined with IV methylprednisolone pulse therapy followed by oral prednisone taper. 1, 2

Induction Regimen Components

Glucocorticoid Dosing

• IV methylprednisolone pulse: 500-1000 mg daily for 1-3 consecutive days at treatment initiation 1, 3
• Oral prednisone: Start at 0.3-0.5 mg/kg/day (maximum 60 mg/day), then aggressively taper to ≤7.5 mg/day by 3-6 months 1, 2
• Never exceed 1 mg/kg/day or 60 mg/day—higher doses provide no additional benefit and accelerate damage 2

Cyclophosphamide Dosing Options

Low-dose regimen (preferred for most patients):

• 500 mg IV every 2 weeks for 6 doses 1, 2
• Total cumulative dose: 3 grams over 3 months
• Comparable efficacy to high-dose protocols with significantly lower gonadotoxicity 2
• Proven effective in diverse populations with 10-year follow-up data 1

High-dose regimen (reserved for high-risk patients):

• 0.5-0.75 g/m² IV monthly for 6 months 1
• Consider only for patients with adverse prognostic factors: 1
  • GFR 25-80 mL/min with nephritic sediment
  • Crescents or fibrinoid necrosis in >25% of glomeruli on biopsy
  • Tubular atrophy/interstitial fibrosis

Specific Indications by Organ System

Proliferative Lupus Nephritis (Class III/IV)

• Low-dose IV cyclophosphamide is first-line alongside mycophenolate mofetil 1
• Expect proteinuria improvement by 3 months, ≥50% reduction by 6 months, and <0.5-0.7 g/24 hours by 12 months 1
• High-dose regimen reserved only for patients with crescents, necrosis, or severely reduced GFR 1

Neuropsychiatric Lupus

• IV cyclophosphamide plus glucocorticoids for inflammatory/immune-mediated manifestations (seizures, psychosis, myelitis, peripheral neuropathy, optic neuritis, brain stem disease) 1
• 18/19 patients (95%) responded to cyclophosphamide versus 7/13 (54%) with methylprednisolone alone in controlled trial 1
• Complete recovery or recovery with minor residuals in 8/9 patients with severe CNS lupus treated with pulse cyclophosphamide 4

Diffuse Alveolar Hemorrhage

• Immediate IV methylprednisolone 250-1000 mg daily for 1-3 days 3
• IV cyclophosphamide 750 mg/m² immediately—this is organ-threatening and requires most potent agents 3
• Do not delay treatment waiting for bronchoscopy if clinical presentation strongly suggests DAH 3

Essential Precautions and Concurrent Therapy

Mandatory Co-Administration

• Hydroxychloroquine: All patients must receive ≤5 mg/kg real body weight unless contraindicated—improves survival even in severe disease 1, 3, 2
• Mesna: Administer with IV cyclophosphamide for bladder protection 1
• Infection prophylaxis: Mandatory given intensive immunosuppression (PCP prophylaxis, consider antiviral) 3, 2

Fertility Preservation

• Gonadotropin-releasing hormone agonists (leuprolide): Offer to reproductive-age women desiring future childbearing 1, 2
• Sperm banking: Safer alternative for men than high-dose testosterone 1
• Oocyte cryopreservation: Alternative but delays cyclophosphamide initiation 1
• Low-dose regimen (500 mg q2weeks × 6) has significantly lower gonadotoxicity than high-dose protocols 2

Cumulative Dose Limits

• Limit lifetime cyclophosphamide exposure to <36 grams to reduce malignancy risk 2
• Risk sharply increases at cumulative doses around 60 grams 2
• Increased risk for herpes zoster, bladder cancer, lymphoma, and other malignancies 1, 5

Monitoring Response and Managing Inadequate Response

Expected Timeline

• By 3 months: Evidence of improvement in proteinuria with GFR normalization/stabilization 1
• By 6 months: At least 50% reduction in proteinuria (partial response) 1
• By 12 months: Proteinuria <0.5-0.7 g/24 hours (complete response) 1
• For nephrotic-range proteinuria at baseline, extend timeframes by 6-12 months 1

Inadequate Response

• Improvement should occur within 3-4 weeks; no improvement or worsening warrants immediate evaluation 2
• After 3-4 months of suboptimal improvement, consider: 2
  • Repeat kidney biopsy to distinguish chronic from active lesions
  • Switch to alternative therapy (mycophenolate mofetil)
  • Exclude non-adherence, infection, or other causes of treatment failure

Common Pitfalls to Avoid

• Do not use oral cyclophosphamide: IV dosing has lower cumulative exposure, fewer adverse events, and requires less frequent neutropenia monitoring (monthly vs weekly) 1
• Do not omit cyclophosphamide in organ-threatening disease: Severe manifestations require the most potent immunosuppression upfront 3
• Do not use high-dose glucocorticoids unnecessarily: Doses >1 mg/kg/day provide no additional benefit and accelerate damage accrual 2
• Do not delay fertility counseling: Must occur before initiating therapy, as gonadotoxicity is dose-dependent and cumulative 2
• Do not skip infection screening: Aggressively exclude infection before initiating immunosuppression, especially in DAH where infection is a major competing diagnosis 3

Maintenance Therapy After Induction

After 6 months of cyclophosphamide induction, transition to maintenance therapy with: 1

• Mycophenolate mofetil 1-2 g/day (preferred) or
• Azathioprine 2 mg/kg/day
• Continue for minimum 3 years after achieving complete response 1

Relapse rates of 10-50% are common; failure to achieve complete remission increases subsequent relapse risk (HR 6.2) 2. Treat relapses with the same initial therapy that achieved the original response 2.