OBJECTIVE To test whether Rituximab (RTX) is efficacious to achieve complete renal response (CR) in Lupus Nephritis (LN) patients with persistent proteinuria (≥1g/d) despite at least 6 months of standard of care (SOC).

STUDY DESIGN Investigator-initiated randomized international open multicentric 104-week study.

After screening (week -8), patients enter in a run-in period of 6 weeks during which treatment is unchanged. At week -2, if persistent proteinuria is confirmed (uP/C ratio ≥1 expressed in mg/mg), patients will be randomized in a 1/1 ratio to 1 of 2 treatment groups as follows :

RTX group Subjects will receive a RTX infusion (1g) at w0, w2, w24, w48 and w72.Control group Subjects will not receive RTX infusions. In both arms, azathioprine (AZA) or mycophenolate mofetil (MMF) will be continued. If prescribed, prednisolone dose should not be > 10 mg/day.

Inclusion Criteria:

All the following inclusion criteria are to be met :

1. SLE, according to ACR and/or SLICC (Arthritis Rheum 2012; May 2; doi: 10.1002/art.34473) criteria ;

2. Age ≥15y (except if local ethics committee imposes ≥18y) ;

3. ISN/RPS 2003 Class III (A or A/C), IV (A or A/C ; S or G) or V lupus GN confirmed on renal biopsy performed within 24 months before screening ;

4. Having received one out of four following immunosuppressive regimens:

   i): Euro-Lupus (EL) intravenous (IV) cyclophosphamide (CY) (6x 500 mg q2w) followed by AZA/MMF for 3 months ; ii): NIH IVCY for 6M (6 monthly pulses) followed by AZA/MMF for 3 months ; iii): MMF for at least 6 months at a dose of 2g/day (or the maximal tolerated dose; iv): AZA for at least 6 months at a dose of 2 mg/kg/day (or the maximal toerated dose).

   All patients should be on AZA or MMF at screening. In all regimens, MMF can be replaced by enteric-coated mycophenolic acid (eMPA) ;

5. If on GC, being on maximum 10 mg equivalent prednisolone/d at screening (for at least 2 weeks) ;

6. uP/C ratio ≥1 (expressed in mg/mg) measured in a 24-h urine collection, confirmed at randomization (w-2) ;

7. Contraception (any type ; sexual abstinence is an alternative to contraception in paediatric patients) ;

8. Signed informed consent (drafted according to local practice and approved by the local ethics committee).

Exclusion Criteria:

Any of the following :

1. Recent or ongoing renal flare defined as either i) : fall in estimated glomerular filtration rate (eGFR ; MDRD) ≥25% within 3 month prior to screening or between screening and randomization ; or ii) : increase in urine protein by ≥100% to >3.5g/d compared to previous assessment ;
2. 24-h proteinuria decline >50% over previous 6 months ;
3. Treatment with ≥10 mg equivalent prednisolone/d in the last 2 weeks before screening ;
4. Pregnancy or breast-feeding ;
5. Anticipated non-compliance with the protocol ;
6. History of malignancy (except non-melanoma skin and cervical intraepithelial cancer) ;
7. Previous treatment with RTX (whenever) and previous treatment with another biologic agent within the last 6 months ;
8. HIV infection ;
9. Active HBV/HCV/TB infection ;
10. Severe liver, cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, haematologic or psychiatric disturbances, that would contraindicate inclusion in the protocol, as judged by the clinician.