Lupus Nephritis: Current Perspectives and Moving Forward

Figures & data

Figure 1 Diagram showing the immunopathogenic pathways leading to kidney damage in LN and presenting novel therapies targeting specific pathways.

Abbreviations: DC, dendritic cell; pDC, plasmacytoid dendritic cell, APRIL, a proliferating-inducing ligand; BAFF, B cell activating factor; BAFFR, B cell activating factor receptor; BCMA, B cell maturation antigen; BTK, Bruton’s tyrosine kinase; CD, cluster of differentiation; IFN, interferon; IFNRI, interferon-type I receptor; JAK, Janus kinase; MHC, major histocompatibility complex; NETs, neutrophil extracellular traps; TACI, transmembrane activator and calcium modulator and cyclophilin ligand interactor; PRR, pattern recognition receptors, TLR, toll-like receptor; DAMPs, damage associated molecular patterns, PAMPs, pathogen associated molecular pattern; IL, interleukin; PAD, peptidylarginine deiminases.

Table 1 Relevant Clinical Trials in Patients with Lupus Nephritis

Target	Drug	Trials	Outcome
B cells Surface antigens (eg, CD20, CD19, CD38)	Rituximab (chimeric anti-CD20 mAb)	EXPLORER, LUNAR	Added to standard induction treatment, did not show renal benefits in active LN patients Role in refractory or frequently relapsing disease, high-risk patient groups (eg Afro-Americans), or corticosteroid minimization
	Obinutuzumab (humanized type 2 anti-CD20 mAb)	NOBILITY, (NCT02550652) REGENCY (NCT04221477) OBILUP (NCT04702256)	Added to background immunosuppression comprising mycophenolate and corticosteroids, increased the rate of achieving primary and secondary efficacy endpoints, possibly related to a rapid and complete depletion of peripheral, memory, and naïve B cell subsets and plasmablasts
	Ocrelizumab (humanized anti-CD20 monoclonal antibody)	BEGIN (NCT00539838) BELONG study (NCT00626197)	Terminated due to no benefit and to higher rate of infections
	Ofatumumab (humanized anti-CD20 antibody)	Case reports	Could represent an alternative treatment for LN patients No RCTs so far
	Obexelimab/XmAb5871 (humanized anti- CD19 mAb)	Phase II clinical trial (NCT02725515)	Treatment in non-organ-threatening SLE patients did not meet the primary endpoint, No phase III clinical trial planned
	Daratumumab (IgG1k mAb against CD38)	Phase II study LN (NCT04868838) Phase II study refractory SLE DARALUP (NCT04810754)	Ongoing trials in refractory SLE patients and in patients with active LN
Survival factors (eg, BAFF, Blys/APRIL, ICOSL, CD40)	Belimumab (humanized anti- BAFF mAb)	BLISS-52 and −76 trials BLISS-LN(NCT01639339)	Efficacy in SLE patients, patients with active LN treated with belimumab plus standard induction treatment had superior renal response compared with placebo
	Tabalumab (humanized mAb against soluble and membrane-bound BAFF)	ILLUMINATE-1 and −2	2 phase III trials with patients with moderate-to-severe SLE without nephritis did not meet the primary endpoint
	Atacicept (fusion protein between TACI and Fc portion of IgG)	APRIL-LN; NCT00573157	Patients with active LN, terminated early due to severe Infections associated with hypogammaglobulinemia
	Blisibimod/A-623 (BAFF inhibitor)	Phase III trial CHABLIS-SC1 (NCT01395745)	Treatment in active SLE patients without nephritis did not meet the primary endpoint, but beneficial in steroid reduction, proteinuria and biomarker responses
	Telitacicept/RC18 (novel recombinant TACI-Fc fusion protein), BLyS/APRIL dual inhibitor	Phase IIb study (NCT02885610) Phase III trial (NCT04082416)	Beneficial in active SLE patients without nephritis in addition to standard therapy, approved in China for active SLE
	Rozibafusp Alfa/AMG570 (anti-ICOSL monoclonal antibody)	Phase II trial (NCT04058028)	Ongoing trial in active SLE patients without nephritis
	AMG 557 (anti-ICOSL monoclonal antibody)	Phase I study (NCT01683695)	Safety and potential efficacy in patients with systemic lupus erythematosus (SLE) with arthritis
	BI655064 (humanized anti- CD40 mAb)	Phase II clinical trial (NCT02770170)	Efficacy and safety of BI655064 in combination with standard of care therapy in active LN patients
Intracellular functions (eg Proteasome inhibitor, BTK inhibitor, transcription factors Ikaros and Aiolos)	Bortezomib (Proteasome inhibitor)	Phase II study (NCT02102594)	Preliminary data showed efficacy in patients with refractory LN, high rates of treatment discontinuation because of poor drug tolerability
	Fenebrutinib (BTK inhibitor)	Phase II RCT (NCT02908100)	Patients with moderate or severe active SLE, reduction in CD19+ B cells, anti-dsDNA levels, but did not meet the primary clinical efficacy endpoint (SRI-4)
	Iberdomide (CC-220) (a cereblon modulator targeting Ikaros and Aiolos)	Phase IIa study (NCT02185040)	Reduced the activity of the type I IFN gene signature and B cell activation. Improved arthritis and CLASI activity scores in SLE patients
T cells	Abatacept (CTLA4)	Phase III ALLURE trial	In addition to standard of care in active LN patients did not increase renal response rate, but improved proteinuria and serological parameters
	Dapirolizumab pegol (pegylated Fab anti-CD40L)	Phase II trial (NCT02804763), Phase II trial (NCT04294667)	Patients with moderate to severe SLE without nephritis, did not meet the primary endpoint
CNI	Tacrolimus		Multi-immunosuppressive regimens with tacrolimus had higher short-term response rate and often superior proteinuria reduction
	Voclosporin	Phase II study (AURA-LV; NCT02141672), Phase III study (AURORA; NCT03021499)	Active LN patients, combined with corticosteroids and MMF showed superior renal response rates and proteinuria reduction
mTOR	Sirolimus	Single-arm phase I/II study (NCT00779194)	In active SLE patients without nephritis or life-threatening lupus complications treatment decreased disease activity, alternative drug for patients with history of malignancy
IFN/IL	Anifrolumab (humanized mAb to type I IFNR)	Phase III TULIP-1 and −2 trials TULIP-LN (NCT02547922)	In moderate-to-severe SLE patients with active disease, especially in those with high type I IFN signatures with improved outcome. Decreased NET formation. In active LN primary endpoint was not met, but improvements in secondary endpoints, including complete renal response
	Secukinumab (humanized anti- IL-17 mAb)	Phase III study (SELUNE, NCT04181762)	Ongoing trial in patients with refractory LN
	Low-dose IL-2	Phase II trial (NCT02465580), Phase II trial (NCT02932137)	Low-dose IL-2 in active SLE patients did not meet its primary endpoint of SRI-4 at 12 weeks. In patients with LN higher complete remission
	Baricitinib (JAK1/2 inhibitor)	Phase II RCT (NCT02708095)	Improved arthritis in active SLE patients
	Tofacitinib (JAK/STAT inhibitor)	Phase I study (NCT02535689)	Improved cardiometabolic and immunologic parameters
Complement	LNP023/ Iptacopan (factor B inhibitor)	Phase II trial (NCT05268289)	Ongoing study in patients with active LN
	OMS721 (MASP-2 inhibitor)	Phase II study (NCT02682407)	In LN patients reduction in proteinuria and faster steroid dose tapering