From the Guidelines
Triple therapy for lupus nephritis should include glucocorticoids, mycophenolic acid analogs (MPAA), and either a calcineurin inhibitor (CNI) or belimumab, as recommended by the KDIGO 2024 clinical practice guideline for the management of lupus nephritis 1. The standard regimen includes high-dose glucocorticoids, such as prednisone starting at 0.5-1 mg/kg/day, gradually tapered over months.
- The immunosuppressant component can be either mycophenolate mofetil (2-3 g/day in divided doses) or low-dose intravenous cyclophosphamide.
- The third component can be either a CNI, such as cyclosporine or tacrolimus, when kidney function is not severely impaired (i.e., estimated glomerular filtration rate [eGFR] ≥ 45 ml/min per 1.73 m²), or belimumab, which can be used in combination with MPAA or low-dose intravenous cyclophosphamide 1. This triple approach targets different aspects of the autoimmune process, with glucocorticoids rapidly reducing inflammation, immunosuppressants preventing immune complex formation and deposition in the kidneys, and CNIs or belimumab providing additional immunomodulatory effects while reducing flare risk. Regular monitoring of kidney function, complete blood counts, and drug levels is essential, along with preventive measures like bone protection for patients on long-term steroids and Pneumocystis pneumonia prophylaxis for those on significant immunosuppression 1.
From the FDA Drug Label
The patients had a clinical diagnosis of SLE according to American College of Rheumatology classification criteria; biopsy-proven lupus nephritis Class III, IV, and/or V; and had active renal disease at screening requiring standard therapy: corticosteroids with 1) mycophenolate for induction followed by mycophenolate for maintenance, or 2) cyclophosphamide for induction followed by azathioprine for maintenance.
The triple therapy for lupus nephritis is:
- Corticosteroids
- Mycophenolate (for induction and maintenance)
- Belimumab (BENLYSTA 10 mg/kg) 2 or
- Corticosteroids
- Cyclophosphamide (for induction)
- Azathioprine (for maintenance)
- Belimumab (BENLYSTA 10 mg/kg) 2
From the Research
Triple Therapy for Lupus Nephritis
The triple therapy for lupus nephritis typically consists of a combination of medications aimed at achieving additive or synergistic therapeutic effects while minimizing toxicity 3. The most commonly used triple therapy regimen includes:
- High-dose corticosteroids
- Mycophenolate mofetil (MMF)
- A calcineurin inhibitor (CNI), such as tacrolimus, at a low dose
Rationale and Efficacy
The rationale behind this combination therapy is to quickly achieve a complete remission and maintain that response long-term while minimizing drug toxicity and preventing tissue damage and death 3. Studies have shown that the addition of a CNI to corticosteroids and MMF can increase the renal response rate in lupus nephritis due to proteinuria reduction 4.
Key Components
The key components of the triple therapy regimen are:
- High-dose corticosteroids: used to reduce inflammation and suppress the immune system
- Mycophenolate mofetil (MMF): an immunosuppressive drug that inhibits the proliferation of T and B lymphocytes
- Calcineurin inhibitor (CNI): a class of immunosuppressive drugs that inhibit the activity of calcineurin, a protein involved in the activation of T lymphocytes
Safety and Efficacy
Studies have demonstrated the safety and efficacy of the triple therapy regimen in patients with lupus nephritis. For example, a cohort study of patients with class III/IV/V lupus nephritis found that the addition of tacrolimus to MMF and prednisolone resulted in significant proteinuria reduction and sustained disease quiescence 4. Another study found that a combination of medium-dose prednisone, methylprednisolone pulses, cyclophosphamide, and hydroxychloroquine was effective in achieving remission of lupus nephritis with less toxicity compared to high-dose prednisone regimens 5.
Comparison with Other Therapies
Comparative studies have also been conducted to evaluate the efficacy of different therapies for lupus nephritis. For example, a randomized, open-label, noninferiority trial found that mycophenolate mofetil was more effective than intravenous cyclophosphamide in inducing remission of lupus nephritis, with a more favorable safety profile 6.