What are the key trials in lupus nephritis (Systemic Lupus Erythematosus nephritis) treatment?

Key Clinical Trials in Lupus Nephritis Treatment

The essential trials you must know for lupus nephritis treatment are ALMS (Aspreva Lupus Management Study), BLISS-LN (Efficacy and Safety of Belimumab in Patients with Active Lupus Nephritis), AURORA 1 and 2 (voclosporin trials), and MAINTAIN Nephritis. These trials have fundamentally shaped current treatment guidelines and established the evidence base for both conventional and novel therapies 1.

Foundational Trials for Conventional Therapy

ALMS Trial (Aspreva Lupus Management Study)

• The largest trial demonstrating mycophenolate mofetil (MMF) equivalence to cyclophosphamide for induction therapy in class III-IV lupus nephritis 1
• Compared MMF (target dose 3 g/day) versus intravenous cyclophosphamide (0.5-1 g/m² monthly pulses) both for 6 months 1
• Showed comparable response rates between the two agents, establishing MMF as first-line therapy 1
• Critical finding: MMF demonstrated more favorable gonadal toxicity profile than cyclophosphamide, which became a major factor in treatment selection 1
• This trial formed the basis for recommending MPA (mycophenolic acid analogs) as initial treatment for most cases of class III-IV lupus nephritis 1

MAINTAIN Nephritis Trial

• Evaluated maintenance therapy comparing MMF versus azathioprine after induction therapy 2
• Demonstrated that both oral MMF and oral azathioprine were superior to continued intravenous cyclophosphamide for maintenance therapy 2
• Showed reduced toxicity with oral agents compared to continued cyclophosphamide every third month 2
• Provided critical evidence on dosage and duration of maintenance treatment with these agents 2

Novel Biologic Trials

BLISS-LN Trial (Belimumab in Lupus Nephritis)

• The pivotal trial that led to FDA approval of belimumab for lupus nephritis in December 2020 1
• Enrolled 448 adult patients with active lupus nephritis (class III, IV, V, and mixed) 1
• Primary endpoint at 104 weeks: belimumab achieved 43% primary efficacy renal response (PERR) versus 32% with placebo (odds ratio 1.6; P = 0.03) when added to standard therapy 1
• PERR defined as: protein-creatinine ratio <0.7, eGFR no worse than 20% below baseline or ≥60 ml/min per 1.73 m², and no treatment failure 1
• Treatment continued until 100 weeks with assessment at week 104 1
• Open-label extension study of 28 weeks (257 patients) showed sustained efficacy benefit with no increase in adverse events 1
• Post hoc analysis demonstrated belimumab-treated patients had fewer lupus nephritis flares and slower decline in kidney function 1
• Triple therapy with belimumab worked best on background of MMF and in patients with non-nephrotic range proteinuria 1

AURORA 1 and AURORA 2 Trials (Voclosporin)

• Phase 3 trial leading to FDA approval of voclosporin in January 2021 for active lupus nephritis 1
• AURORA 1: Primary endpoint assessed at week 52 in adults with active lupus nephritis (classes III, IV, V, and mixed) 1
• Voclosporin plus standard therapy was more effective than standard therapy alone 1
• AURORA 2: Two-year continuation study (116 voclosporin patients, 100 control patients) 1
• Showed sustained reduction of proteinuria with stable kidney function in both groups, with no safety signal 1
• Many patients had voclosporin dose reduction during the 2-year extension, which may have positively impacted eGFR readings 1
• Significantly glucocorticoid-sparing regimen, reducing glucocorticoid adverse events during lupus nephritis treatment 1
• For class V lupus nephritis specifically, voclosporin plus standard therapy showed better efficacy but did not quite reach statistical significance, possibly due to small patient numbers 1

Important Caveats About These Trials

Trial Design Considerations

• Early trials of immunosuppressive agents highlighted the importance of long-term follow-up (beyond 5 years) to demonstrate differences in hard outcomes like doubling of serum creatinine, end-stage renal disease, and death 1
• These hard outcomes are infrequent and occur late in the disease course 1
• Intermediate outcome measures (renal response and flares) occurring within first 2 years correlate with hard outcomes in long-term studies and are commonly used as trial endpoints 1
• However, correlation does not guarantee surrogacy for all patients—some may have hard outcomes diverging from intermediate outcomes 1

Limitations in Evidence Base

• Long-term data beyond 2-3 years are not yet available for mycophenolic acid analogs despite widespread use 1
• Trials typically excluded patients with severe active lupus nephritis and severe active CNS lupus 3
• Class V (membranous) lupus nephritis remains without definitive recommendations from trials, with only suggested practice points 1
• Small numbers of class V patients in belimumab and voclosporin trials limit conclusions for this population 1

Population-Specific Findings

• Subgroup analysis suggests MMF may have greater efficacy in patients of African descent, though further confirmation is needed 1
• Low-dose cyclophosphamide regimen (total dose 3 g over 3 months) has not been tested in pure class V lupus nephritis 1

Clinical Application of Trial Evidence

Current Treatment Paradigm Based on Trials

• ALMS established MMF as preferred induction therapy over cyclophosphamide for most class III-IV lupus nephritis cases 1
• BLISS-LN and AURORA trials introduced triple therapy concept: adding belimumab or voclosporin to standard therapy (glucocorticoids plus MMF) 1
• MAINTAIN trial established MMF or azathioprine as maintenance therapy options 2

Choosing Between Novel Agents

• Voclosporin may be preferred in patients with relatively good kidney function (eGFR ≥45 ml/min per 1.73 m²) who have heavy proteinuria due to podocyte injury 1
• Belimumab may be preferred in patients at high risk of lupus nephritis flare or with advanced CKD likely to progress 1
• Belimumab has demonstrated efficacy in extrarenal lupus with a long track record 1
• Voclosporin requires monitoring for acute eGFR variations 1