Lupus Nephritis, Systemic Lupus Erythematosus (SLE)
Conditions
Keywords
Lupus Nephritis, LN, SLE, Systemic lupus erythematosus, volcosporin, mmf, cellcept, prednisolone, kidney biopsy
Brief summary
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.
Interventions
PROCEDUREKidney Biopsy
At 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.
Arm 1 will receive triple therapy (addition of voclosporin)
DIAGNOSTIC_TESTBlood, feces and urine sample collection
Blood, feces and urine samples will be collected at multiple timepoints during study follow-up period.
OTHERLupusPRO questionnaire
The 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.
MMF 1000 mg twice daily (or 500 mg four times daily)
DRUGPrednisolone
Following intravenous methylprednisolone induction (500mg, 3 days), oral prednisolone 1 mg/kg/day tapered to ≤5 mg/day within 3 months.
Sponsors
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
16 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
Lupus nephritis patients Inclusion Criteria: * 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
Exclusion criteria
* 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) * History of hepatitis B, hepatitis C, tuberculosis and/or HIV * Treatment with any of the following agents within one month before screening: tacrolimus, belimumab, anifrolumab - Treatment with any of the following agents within 6 months before screening: rituximab, daratumumab, eculizumab * Prolongation of QT-interval (QTc \>470ms) and/or bradycardia (resting heart rate \<50bpm) measured on two separate occasions * Hyperkalaemia (serum potassium \>6.0 mmol/L) * Hypertension (blood pressure \> 165/105 mmHg, with symptoms of hyperten sion)\* * Co-administration of voclosporin with strong CYP3A4 inhibitors (e.g., ke toconazole, itraconazole, clarithromycin) * Pregnancy * A single elevated blood pressure measurement will not lead to immediate exclusion from the trial. Antihypertensive therapy may be initiated as appropriate. Dose adjustments of voclosporin should be made in accordance with Section 11.3.2 of the protocol SLE patients without LN (disease control group) Inclusion criteria * Diagnosis of SLE according to EULAR/ACR guidelines * Age 16-70
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Determining single cell RNA sequencing differences within the full macrophage spectrum between arm 1 vs arm 2 | From enrollment to the repeat kidney biopsy at 3 months after starting treatment | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Analyze rapid clinical remission of intensified treatment by proteinuria levels for relation to tissue changes | From enrollment to the end of follow-up at 24 months | Clinical remission achievement will be related to transcriptomic tissue signature |
| Assess differences in macrophage subtypes within kidney tissue | From enrollment to the repeat kidney biopsy at 3 months after starting treatment | 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 | From enrollment to the repeat kidney biopsy at 3 months after starting treatment | 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 | From enrollment to the end of follow-up at 24 months | 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. |
| To identify potential non-invasive urinary biomarkers | From enrollment to the end of follow-up at 24 months | To identify potential non invasive urinary biomarkers of disease activity in the scRNA-seq data, to be tested in sequentially stored urine and/or serum from patients |
| Confirm scRNA-seq identified macrophage markers immunohistochemically, identify spatial distribution (glomerular vs interstitial) and assess their predictive and prognostic use. | From enrollment to the end of follow-up at 24 months | — |
Countries
Netherlands
Outcome results
None listed