Chapter 17 Lupus nephritis

17.1 Induction

Induction regimes using cyclophosphamide are more effective than steroids alone:

Austin et al. (1986): - IV CYC plus steroids vs. steroids alone in lupus nephritis. Cyclophosphamide delayed progression to ESRF.

NIH study (1996): - pulsed IV CYC vs. pulsed IV steroids vs. both in proliferative lupus nephritis. Steroids alone were less effective at inducing remission.

Euro-Lupus (2002) and 10-yr follow-up (2010): - high-dose vs. low-dose cyclophosphamide induction (with azathioprine maintenance) in proliferative lupus nephritis. Low-dose regime was non-inferior.

MMF for induction is non-inferior to cyclophosphamide:

Ginzler et al. (2005): - MMF vs. IV cyclophosphamide in lupus nephritis (class III–V). MMF was more effetive than cyclophosphamide at inducing remission.

ALMS (2009): - MMF vs. IV cyclophosphamide in lupus nephritis (class III–V). MMF was non-inferior.

Post-hoc subgroup analysis or ALMS suggest MMF may be superior when GFR <30. On the other hand meta-analyses suggests greater relapse rate after MMF.

Contemporary protocols favour relatively less steroid:

MYLUPUS (2011): - standard-dose (starting ~1 mg/kg/day) vs. low-dose (starting ~0.5 mg/kg/day) pred in proliferative LN. Both groups treated with enteric-coated mycophenolate (~720 mg bd then tid). Small study (n = 40 + 40) but similar efficacy at inducing remission by 6 months.

17.2 Maintenance & adjunctive Rx

MMF is superior to aza in maintenance: Dooley et al. (2011): - MMF (2g/day) vs aza (2 mg/kg/day) for maintenance of remission in lupus nephritis. MMF superior at maintaining remission (treatment failure during 3 year follow-up ~16 vs 32%) and associated with fewer serious adverse events.

Canadian HCQ trial (1991): - withdrawal vs continuation of HCQ in stable lupus. Withdrawal lead to ~2.5x risk of lupus flare.

17.3 Newer therapies

17.3.1 B-cell therapies

Rituximab may be an alternative option in steroid-sparing regimes and for rescue therapy.

LUNAR (2012): - rituximab vs. placebo in proliferative lupus nephritis (alongside MMF and steroids). No difference in primary end-point (of renal response at 1 year).

RITUXILUP - not yet reported.

Belimumab targets B-cell activating factor (BAFF, aka B-lymphocyte stimulator, BLyS).

BLISS-LN (2020): - belimumab vs placebo (plus standard induction with CYC / MMF) in lupus nephritis. Primary outcome was changed after study registration. Final primary outcome was uPCR < 100 with stable eGFR and no rescue Rx at 2 yrs. Belimumab was efficacious (40 vs. 30% primary end-point) with good safety profile. The results would not have been statistically significant for the original primary end-point (complete / partial / non-response).

17.3.2 CNIs

Multi-target therapy (2015): - tacro + MMF + steroid vs IV CYC + steroid in Chinese population (n = 368). Tacro and MMF induced greater complete remission (25 vs 45 %) at 24 weeks.

AURORA (2021): - voclosporin vs placebo in lupus nephritis, in addition to MMF and pred. Primary endpoint was complete renal remission at 1 yr. Voclosporin was effective (primary endpoint in ~40 vs. 20%) with no safety signal. Primary endpoint dominated by proteinuria response which may of course be haemodynamic.

17.4 Glucocorticoid toxicity

Apostolopoulos et al. (2020): - cohort study in South-East Asia / Australasia (n = 1700): in patients with SLE (of whom 50% had baseline kidney disease - not necessarily lupus nephritis), glucocorticoid use was associated with damage accrual, independent of disease activity.

17.5 Contraception

Petrie et al. & Sanchez-Guerro et al. (2005): - two RCTs testing contraceptive methods in women with SLE. Only patients with inactive or stable disease recruited; excluded if APS or prior VTE. Use of estrogen-containing contraceptives did not provoke disease flare.