The goal of this clinical trial is to learn how different treatments affect immune cells in the kidney in people with active lupus nephritis (LN), a kidney manifestation of systemic lupus erythematosus (SLE). It will also investigate whether early changes in kidney tissue can predict long-term treatment response and whether blood or urine biomarkers can be used to monitor disease activity without the need for repeat kidney biopsies.
The main questions it aims to answer are:
* Does adding voclosporin to standard treatment with mycophenolate mofetil (MMF) and prednisolone result in greater early improvement of kidney inflammation compared with MMF and prednisolone alone? * Are specific macrophage and monocyte populations associated with treatment response and long-term kidney outcomes? * Can blood- or urine-based biomarkers be identified that reflect kidney inflammation and treatment response?
Researchers will compare MMF, prednisolone, and voclosporin (triple therapy) with MMF and prednisolone alone (dual therapy) to determine whether intensified treatment leads to faster and more complete immunological and histological remission.
Participants with newly diagnosed or relapsing proliferative lupus nephritis will:
* Be randomly assigned to receive either triple therapy (MMF, prednisolone, and voclosporin) or dual therapy (MMF and prednisolone). * Undergo a kidney biopsy before treatment starts and a repeat kidney biopsy after 3 months of treatment. * Provide blood and urine samples during follow-up for immune cell analyses and biomarker studies. * Complete patient-reported outcomes questionnaires * Attend regular study visits and clinical assessments for up to 2 years.
In addition, participants with SLE without lupus nephritis and healthy volunteers will provide blood samples to allow comparison of circulating immune cell populations between groups.
Patients with de novo or flaring SLE according to the EULAR/ACR criteria and a suspicion of class III or IV LN with a clinical indication to perform a kidney biopsy
Age 16-70 years
eGFR as measured by cystatin C >20 mL/min
LN class I, II or pure class V upon kidney biopsy
eGFR as measured by cystatin C <20 mL/min
Histological chronicity score (NIH) of 8 or higher in the kidney biopsy
Active infection of any kind as evidenced by cultures (blood, urine or otherwise)
Parallel
Kidney Biopsy
Procedure/SurgeryAt 3 months after the start of treatment, participants will undergo a repeat renal biopsy for assessment of early histological response and for single-cell RNA sequencing.
Voclosporin (LUPKYNIS)
DrugArm 1 will receive triple therapy (addition of voclosporin)
Blood, feces and urine sample collection
Diagnostic testBlood, feces and urine samples will be collected at multiple timepoints during study follow-up period.
LupusPRO questionnaire
Other interventionThe lupusPRO v1.7 questionnaire (20) is a 43-question patient reported outcome survey tool to follow the impact of lupus or its treatment on the patient's quality of life. The questionnaire takes 7-8 minutes to complete and is validated and available in multiple languages. Participants will be asked to either fill in the questionnaire at home (and bring it on their next outpatient clinic visit) or while visiting the hospital during follow-up time. The questionnaires are filled in on paper.
Mycophenolate Mofetil (MMF) Treatment
DrugMMF 1000 mg twice daily (or 500 mg four times daily)
Prednisolone
DrugFollowing intravenous methylprednisolone induction (500mg, 3 days), oral prednisolone 1 mg/kg/day tapered to ≤5 mg/day within 3 months.
Determining single cell RNA sequencing differences within the full macrophage spectrum between arm 1 vs arm 2
The macrophage spectrum will be compared between baseline kidney biopsy and kidney biopsy at 3 months treatment. Differences in celltype proportions, gene expression and spatial organization will be assessed using spatial single cell RNA sequencing techniques.
Analyze rapid clinical remission of intensified treatment by proteinuria levels for relation to tissue changes
Clinical remission achievement will be related to transcriptomic tissue signature
Assess differences in macrophage subtypes within kidney tissue
Numerically distinguish residential macrophages and monocyte derived macrophages in kidney tissue with spatial scRNAseq, comparing arm 1 vs arm 2.
Assess histological response of both treatment arms
Assessment of histological response of intensified treatment (arm 1) compared to dual therapy (arm 2)
To assess phenotype of circulating monocytes in LN patients compared to SLE patients without clinical kidney involvement and healthy participants
Phenotype of circulating monocytes of LN patients will be associated with kidney tissue signature and compared to circulating monocyte phenotype of SLE patients without clinical kidney involvement and healthy participants.
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