What is the recommended regimen for maintenance immunosuppression?

Maintenance Immunosuppression Regimen

For lupus nephritis, maintenance therapy should consist of mycophenolate mofetil 750-1000 mg twice daily (or mycophenolic acid 540-720 mg twice daily) combined with low-dose glucocorticoids (≤7.5 mg/day prednisone), continued for a minimum total duration of 36 months (induction plus maintenance combined). 1

Primary Maintenance Regimen

Mycophenolate-Based Therapy

• Mycophenolate mofetil (MMF): 750-1000 mg twice daily (1.5-2 grams total daily) during the early maintenance phase 1, 2
• Mycophenolic acid (MPA): 540-720 mg twice daily (1.08-1.44 grams total daily) as the equivalent dose 1, 2
• These doses should be maintained until achievement of complete response, then tapering can be considered 1
• The dose may need reduction when kidney function is significantly impaired, as patients with CKD are more susceptible to MPA adverse effects 1

Glucocorticoid Component

• Low-dose prednisone: 5-7.5 mg/day should be continued for at least 2 years, then slowly reduced by 1 mg every 2 months 1
• Glucocorticoid discontinuation in patients with stable quiescent disease can be considered, but must be undertaken with extreme caution and careful monitoring for disease flare 1
• Abrupt withdrawal after years of use may cause withdrawal symptoms that mimic flares 1

Alternative Maintenance Options

Calcineurin Inhibitor-Based Regimens

• Tacrolimus monotherapy with low-dose glucocorticoids: Target trough blood level of 4-6 ng/mL (5-7.4 nmol/l) 1, 3
• Triple therapy (multitarget): Tacrolimus 2-3 mg/day + MMF 0.5-0.75 g/day + prednisone 10 mg/day has shown similar relapse rates with lower adverse events compared to azathioprine-based regimens 1
• CNIs should be considered particularly in patients intolerant of MMF and azathioprine, though nephrotoxicity must be monitored closely 1

Azathioprine-Based Therapy

• Azathioprine: 1.5-2 mg/kg/day combined with low-dose glucocorticoids (prednisone 5-7.5 mg/day) 1
• Start at 1.5-2 mg/kg/day for 18-24 months, then decrease to 1 mg/kg/day until 4 years after diagnosis, then taper by 25 mg every 3 months 1
• Azathioprine is comparable to MMF when used after Euro-Lupus dosing of intravenous cyclophosphamide, but MMF may be superior when steroids are tapered and stopped during maintenance 1

Critical Duration Requirements

Minimum Treatment Duration

• Total immunosuppression duration (induction + maintenance) must be ≥36 months for patients with proliferative lupus nephritis who have achieved complete renal response and have no ongoing extrarenal manifestations 1
• The WIN-Lupus trial demonstrated more severe SLE flares and a trend toward higher renal relapses when immunosuppression was discontinued before this timeframe 1
• Discontinuation of MMF before 2 years in Chinese patients was associated with increased risk of disease flare 1

Extended Duration Considerations

• Optimal duration is 18 months to 4 years after induction of remission for ANCA-associated vasculitis 1
• For lupus nephritis, many patients require longer than 36 months—a median of 4 years of prior immunosuppressive therapy was a predictor of successful treatment discontinuation in an Italian cohort 1
• Patients who achieved only partial remission tend to be left on maintenance immunosuppression indefinitely 1

Monitoring and Dose Adjustments

Therapeutic Drug Monitoring

• MPA exposure measurement may be helpful in patients with unsatisfactory treatment response or those at increased risk of drug toxicities 1
• During the third to fourth year of MMF maintenance, kidney flare was associated with low 12-hour trough MPA blood levels, whereas patients with trough levels of approximately 2 mg/L (6.2 mmol/L) remained in remission 1
• Target MPA-AUC₀₋₁₂ of 60-90 mg*h/L optimizes outcomes, though routine monitoring is not yet standard practice 2

Tacrolimus Monitoring

• Trough levels should be measured 12 hours after the last dose, targeting 4-6 ng/mL 3
• Close monitoring of blood pressure, kidney function, and electrolytes is required due to dose-dependent nephrotoxicity risk 1

Critical Pitfalls to Avoid

Premature Discontinuation Risks

• 28-50% of patients continued to show inflammatory histologic activity on repeat kidney biopsy despite ≥36 months of immunosuppression and ≥12 months of sustained complete clinical renal response 1
• Patients with persistent histologic activity have an increased risk of lupus nephritis flare after maintenance immunosuppression is discontinued 1
• The ALMS maintenance phase demonstrated a relatively high incidence of treatment failure (16-32%) and kidney flares (13-23%) despite 36 months of immunosuppression 1

Toxicity Considerations

• Calcineurin inhibitor nephrotoxicity is dose-dependent and requires vigilant monitoring, particularly in patients with pre-existing chronic kidney disease 1, 3
• CNIs can reduce proteinuria through nonimmunological mechanisms, so response may not reflect histologic quiescence—repeat biopsies may be needed 1
• Combining tacrolimus with multiple other immunosuppressants without clear indication increases infection risk 3

Pharmacogenetic Variability

• MPA exposure varies considerably among patients receiving the same dose due to pharmacogenetic differences 1
• Asian patients may require only 2 grams/day MMF for equivalent efficacy with potentially better tolerability, while non-Asian patients should aim for 3 grams/day during induction 2

Role of Repeat Kidney Biopsy

• Consider repeat biopsy to inform the decision to continue or withdraw maintenance immunosuppression, as clinical response findings do not correlate completely with ongoing kidney inflammation 1
• Repeat biopsies are helpful to assess for continued histologic activity when considering dose de-escalation 1
• Many patients in partial remission have resolution of histologic activity but clinically remain in partial remission due to residual proteinuria, which may reflect CKD rather than active disease 1